5-substituted indazoles as kinase inhibitors

ABSTRACT

The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, 
                         
wherein A, R 1 , R 2 , R 3  and m, are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), Cdc7, AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

RELATED APPLICATION INFORMATION

This application is a continuation-in-part of U.S. application Ser. No.12/132,993 filed on Jun. 4, 2008 which claims priority to provisionalapplication Ser. No. 60/933,960 filed on, Jun. 8, 2007, the contents ofeach of which are herein incorporated by reference.

TECHNICAL FIELD

The present invention relates to 5-substituted indazole containingcompounds, methods of making the compounds, compositions containing thecompounds which are useful for inhibiting kinases such as GlycogenSynthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), Cdc7,AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

BACKGROUND OF THE INVENTION

Protein kinases are a class of enzymes that catalyze the transfer of aphosphate group from ATP to a tyrosine, serine, threonine, or histidineresidue located on a protein substrate. Protein kinases clearly play arole in normal cell growth. Many of the growth factor receptor proteinshave intracellular domains that function as protein kinases and it isthrough this function that they effect signaling. The interaction ofgrowth factors with their receptors is a necessary event in the normalregulation of cell growth, and the phosphorylation state of substrateproteins often is related to the modulation of cell growth.

It is widely known that abnormal protein phosphorylation may be directlylinked to certain disease states or may be a contributing factor in theonset of such diseases. As a result, protein kinases have become thetargets of new pharmaceutical research (Cohen, P. Nature Reviews DrugDiscovery, 1:309-315, 2002). Various protein kinase inhibitors have beenused clinically in the treatment of a wide variety of diseases, such ascancer, chronic inflammatory diseases, diabetes and stroke.

The protein kinases are a large and diverse family of enzymes thatcatalyze protein phosphorylation and play a key role in cellularsignaling. Protein kinases may exert positive or negative regulatoryeffects, depending upon their target protein. Protein kinases areinvolved in specific signaling pathways which regulate cell functionssuch as, but not limited to, metabolism, cell cycle progression, celladhesion, vascular function, apoptosis, and angiogenesis. As a result,malfunctions of cellular signaling have been associated with manydiseases, the most characterized of which include cancer and diabetes.The regulation of signal transduction by cytokines and the associationof signal molecules with proto-oncogenes and tumor suppressor genes havebeen well documented. Similarly, the connection between diabetes, viralinfections and the conditions related thereto has also been associatedwith the regulation of protein kinases.

Because protein kinases regulate nearly every cellular process,including metabolism, cell proliferation, cell differentiation, and cellsurvival, they are attractive targets for therapeutic intervention forvarious disease states. For example, cell-cycle control andangiogenesis, in which protein kinases play a pivotal role are cellularprocesses associated with numerous disease conditions such as, but notlimited to, cancer, inflammatory diseases, abnormal angiogenesis anddiseases related thereto, atherosclerosis, macular degeneration,diabetes, obesity, and pain.

The elucidation of the intricacy of protein kinase pathways and thecomplexity of the relationship and interaction among and between thevarious protein kinases and kinase pathways highlights the importance ofdeveloping pharmaceutical agents capable of acting as protein kinasemodulators, regulators or inhibitors that have beneficial activity onmultiple kinases or multiple kinase pathways.

It has therefore been suggested that due to the complexity ofintracellular signaling cascades of protein kinase pathways, agents thataffect multiple pathways simultaneously may be required for meaningfulclinical activity. Although it has been suggested that a single agentthat provides combinatorial effects is an attractive notion, there is aneed to identify and use single agents that target the right combinationof multiple pathways that are clinically effective in a particulardisease setting.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase encodedby two isoforms, GSK-3α and GSK-3β with molecular weights of 51 and 47kDa, respectively. These share 97% sequence similarity in their kinasecatalytic domains. The GSK-3α isoform has an extended glycine-richN-terminal tail. A minor splice variant of GSK-3β has been identified(expressed at ˜15% of total) with a 13 amino acid insert within thekinase domain. This variant had a reduced activity towards tau. GSK-3 ishighly conserved throughout evolution, and found in all mammals thus farwith high homology in the kinase domain. Both isoforms are ubiquitouslyexpressed in mammalian tissues, including the brain. PharmacologicalGSK-3 inhibitors are not able to selectively inhibit one of theisoforms.

GSK-3β plays an important role in the control of metabolism,differentiation and survival. It was initially identified as an enzymeable to phosphorylate and hence inhibit glycogen synthase. Subsequently,it was recognized that GSK-3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies.

Interestingly, protein kinase B (AKT) phosphorylation of GSK-3β resultsin a loss of kinase activity, and it has been proposed that thisinhibition may mediate some of the effects of neurotrophic factors.Moreover, phosphorylation of β-catenin (a protein involved in cellsurvival) by GSK-3β, results in its degradation by an ubiquitinilationdependent proteasome pathway.

Therefore it appears that inhibition of GSK-3β activity may result inneurotrophic activity. There is evidence that lithium, an uncompetitiveinhibitor of GSK-3β, enhances neuritogenesis in some models and can alsoincrease neuronal survival, through the induction of survival factorssuch as Bcl-2 and the inhibition of the expression of proapoptoticfactors such as P53 and Bax.

Further studies have shown that β-amyloid increases GSK-3β activity andtau protein phosphorylation. Moreover, this hyperphosphorylation as wellas the neurotoxic effects of β-amyloid are blocked by lithium chlorideand by a GSK-3β antisense mRNA. These observations taken togethersuggest that GSK-3β may be the link between the two major pathologicalprocesses in Alzheimer's disease: abnormal APP (Amyloid PrecursorProtein) processing and tau protein hyperphosphorylation.

These experimental observations indicate that GSK-3β may findapplication in the prevention and treatment of the neuropathologicalconsequences and the cognitive and attention deficits associated withAlzheimer's disease, as well as other acute and chronicneurodegenerative diseases. These include, but are not limited to:Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy) and other dementia including vascular dementia; acute stroke andother traumatic injuries; cerebrovascular accidents (e.g. age relatedmacular degeneration); brain and spinal cord trauma; peripheralneuropathies; retinopathies and glaucoma.

GSK-3β may also have utility in the treatment of other diseases such as:non-insulin dependent diabetes and obesity; manic depressive illness;schizophrenia; alopecia; inflammation; cancers such as breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia andseveral virus-induced tumors.

Rho kinases (ROCKs), the first Rho effectors to be described, areserine/threonine kinases that are important in fundamental processes ofcell migration, cell proliferation and cell survival. Abnormalactivation of the Rho/ROCK pathway has been observed in variousdisorders. Examples of disease states in which compounds of the presentinvention have potentially beneficial therapeutic effects due to theiranti vasospasm activity includes cardiovascular diseases such ashypertension, chronic and congestive heart failure, cardiac hypertrophy,restenosis, chronic renal failure, cerebral vasospasm after subarachnoidbleeding, pulmonary hypertension and atherosclerosis. The musclerelaxing property is also beneficial for treating asthma, male erectiledysfunctions, female sexual dysfunction, and over-active bladdersyndrome. Injury to the adult vertebrate brain and spinal cord activatesROCKs, thereby inhibiting neurite growth and sprouting. Inhibition ofROCKs results in induction of new axonal growth, axonal rewiring acrosslesions within the CNS, accelerated regeneration and enhanced functionalrecovery after acute neuronal injury in mammals (spinal-cord injury,traumatic brain injury). Inhibition of the Rho/ROCK pathway has alsoproved to be efficacious in other animal models of neurodegenerationlike stroke, inflammatory and demyelinating diseases, Alzheimer'sdisease as well as the treatment of pain. Rho/ROCK pathway inhibitorstherefore have potential for preventing neurodegeneration andstimulating neuroregeneration in various neurological disorders,including spinal-cord injury, Alzheimer's disease, stroke, multiplesclerosis, amyotrophic lateral sclerosis, as well as the treatment ofpain. ROCK inhibitors have been shown to possess anti-inflammatoryproperties. Thus, compounds of the invention can be used as treatmentfor neuroinflammatory diseases such as stroke, multiple sclerosis,Alzheimer's disease, Huntington's disease, Parkinson's disease,amyotrophic lateral sclerosis, and inflammatory pain, as well as otherinflammatory diseases such as rheumatoid arthritis, osteoarthritis,asthma, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerativecolitis, Lupus, and inflammatory bowel disease. Since ROCK inhibitorsreduce cell proliferation and cell migration, they could be useful intreating cancer and tumor metastasis. Further more, there is evidencesuggesting that ROCK inhibitors suppress cytoskeletal rearrangement uponvirus invasion, thus they also have potential therapeutic value inanti-viral and anti-bacterial applications. ROCK inhibitors are alsouseful for the treatment of insulin resistance and diabetes. Further,ROCK inhibitors have been shown to ameliorate progression of cysticfibrosis (Abstract S02.3, 8th World Congress on Inflammation,Copenhagen, Denmark, Jun. 16-20, 2007).

In addition, Rho-associated coiled-coil forming protein kinases (ROCK)-1and -2, have been shown to enhance myosin light chain (MLC)phosphorylation by inhibiting MLC phosphatase as well as phosphorylatingMLC. This results in the regulation of actin-myosin contraction. Recentreports have demonstrated that inhibition of ROCK results in disruptionof inflammatory cell chemotaxis as well as inhibition of smooth musclecontraction in models of pulmonary inflammation associated with asthma.Therefore, the inhibitors of the Rho/ROCK pathway should be useful forthe treatment of asthma.

The Janus kinases (JAKs) are an important family of intracellularprotein tyrosine kinases (PTKs), with 4 mammalian members, JAK1, JAK2,JAK3, and TYK2, as well as homologs in chicken, fish, and Drosophila.The JAKs play critical roles in several important intracellularsignaling pathways, including the eponymous JAK/STAT pathway, central tothe mediation of cytokine signaling. It is this pivotal role in cytokinesignaling that underpins the notion that specific JAK inhibitors may betherapeutically deployed in situations where cytokine activity resultsin disease. Important examples of this include autoimmune diseases suchas rheumatoid arthritis and psoriasis, myeloproliferative syndromes suchas, leukemias, lymphomas, and cardiovascular diseases.

JAK2, a member of the Janus kinase (JAK) family of protein tyrosinekinases (PTKs), is an important intracellular mediator of cytokinesignaling. Mutations of the JAK2 gene are associated with hematologiccancers, and aberrant JAK activity is also associated with a number ofimmune diseases, including rheumatoid arthritis.

Aurora kinases are a family of multigene mitotic serine-threoninekinases that functions as a class of novel oncogenes. These kinasescomprise aurora-A, aurora-B, and aurora-B members. These arehyperactivated and/or over-expressed in several solid tumors includingbut not limited to breast, ovary, prostate, pancreas, and colorectalcancers. In particular aurora-A is a centrosome kinase, and itslocalization depends on the cell cycle and plays an important role cellcycle progression and cell proliferation. Aurora-A is located in the20q13 chromosome region that is frequently amplified in severaldifferent types of malignant tumors such as colorectal, breast andbladder cancers. Inhibition of aurora kinase activity could help toreduce cell proliferation, tumor growth and potentially tumorigenesis.

Eukaryotic cells divide by a directed, step-wise process referred to asthe cell cycle. Cells must first replicate their DNA in S phase beforeseparating their sister chromatids in mitosis (karyokinesis) andsplitting off into two daughter cells (cytokinesis). In mammalian cells,DNA replication must be initiated at multiple sites (replicationorigins) throughout the genome to ensure that all the genetic materialis duplicated prior to mitosis. To maintain genome integrity, DNA mustbe replicated only once per cell cycle, and so this process is highlyregulated and governed by checkpoints. Before replication is initiated,origins must be licensed through the formation of pre-replicationcomplexes (pre-RCs) in early G1. Formation of pre-RCs involves thestep-wise binding of the origin recognition complex (ORC) to originsfollowed by the binding of the loading factors Cdc6 and Cdt1. Theseproteins then recruit the putative DNA replicative helicase complex,MCM2-7. Once this pre-RC is formed, replication initiation requires theactivation of S-phase-promoting serine/threonine kinases, Cyclin/Cdksand Cdc7/Dbf4. These kinases consist of an enzymatic subunit (CDKs andCdc7) and a regulatory sub-unit (Cyclins for CDKs; Dbf4 or Drf1 forCdc7). They phosphorylate multiple MCMs in pre-RCs in a sequentialmanner, thereby activating the helicase and recruiting other DNAreplication factors (Cdc45, GINS complex, etc.) for DNA synthesis (forreviews, see Kim, J. M., et al. (2003). Functions of mammalian Cdc7kinase in initiation/monitoring of DNA replication and development.Mutat. Res. 532, 29-40; Kim, J. M., et al. (2004). Genetic dissection ofmammalian Cdc7 kinase: cell cycle and developmental roles. Cell Cycle 3,300-304; Lau, E., et al. (2006). The functional role of Cdc6 in S-G2/Min mammalian cells. EMBO Rep. 7, 425-430; Lau, E., et al. (2007). Therole of pre-replicative complex (pre-RC) components in oncogenesis.Faseb J. 21, 3786-3794; Stillman, B. (2005). Origin recognition and thechromosome cycle. FEBS Lett. 579, 877-884). MCM2 Serine-40 and Serine-53are well-characterized phosphorylation sites for Cdc7/Dbf4 (Cho et al.,2006; Montagnoli et al., 2006; Tsuji et al., 2006).

Inhibiting regulators of replication initiation, such as Cdc6, Cdc7/Dbf4or Cdc7/Drf1, has lethal consequences in cancerous cells, whereas normalcells are able to arrest and resume normal divisions once initiationactivity is restored (Feng, D., et al. (2003). Inhibiting the expressionof DNA replication-initiation proteins induces apoptosis in human cancercells. Cancer Res. 63, 7356-7364; Montagnoli, A., et al. (2004). Cdc7inhibition reveals a p53-dependent replication checkpoint that isdefective in cancer cells. Cancer Res 64, 7110-7116; see Lau, E., et al.(2006). Is there a pre-RC checkpoint that cancer cells lack? Cell Cycle5, 1602-1606, for review). Small molecule inhibitors of the proteinkinase Cdc7 are thus attractive candidates for therapeutic interventionin cancer, inflammation and other cell proliferative disorders.

Accordingly, there remains a need for the development of methodscomprising the use of a single agent drug capable of targeting specificsets of kinases or kinase pathways. In particular such methods affectthe right combination of multiple targets thereby achieving clinicalefficacy.

SUMMARY OF THE INVENTION

In the principle embodiment, the present invention provides compounds ofFormula (I),

or a pharmaceutically acceptable salt thereof, wherein

A is

R₁ is hydrogen, alkoxycarbonyl, alkyl, aryl, heterocycle, heteroaryl,R_(a)R_(b)N—, R_(c)R_(d)N—C(O)— or R_(c)R_(d)N—S(O)₂—;

R₂ is hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl,heterocyclecarbonyl or R_(e)R_(f)N-alkyl-C(O)—;

R₃ is alkyl, alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl,heteroaryl, nitro, or R_(g)R_(h)N—;

R₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle,heterocyclealkyl, R_(j)R_(k)N— or R_(j)R_(k)N-alkyl-;

R₅ is alkyl, aryl, or heteroaryl;

R₆ is alkyl, alkoxyalkyl, R_(j)R_(k)N-alkyl-, aryl, cycloalkyl orheteroaryl;

R₇ is alkyl, aryl or heteroaryl;

R_(a) and R_(b) are each independently hydrogen, alkyl, arylalkyl,cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclealkyl,R₄—C(O)—, or R₅—S(O)₂—;

R_(c), and R_(d) are each independently hydrogen, alkyl or heteroaryl;

R_(e) and R_(f) are each independently hydrogen, alkyl, arylalkyl,heteroarylalkyl, R₆—C(O)—, or R₇—S(O)₂—;

R_(g) and R_(h) are each independently hydrogen, alkyl, oralkylcarbonyl;

R_(j) and R_(k) are each independently hydrogen, alkyl, aryl, arylalkyl,cycloalkyl, heteroaryl, or heterocycle;

R_(i), R_(ii), R_(iii), R_(iv), R_(v), R_(vi), R_(vii), R_(viii),R_(ix), R_(x), R_(xi), R_(xii), R_(xiii), R_(xiv), R_(xv), R_(xvi),R_(xvii), R_(xviii), R_(xix), R_(xx), R_(xxi), R_(xxii), and R_(xxiii)are each independently alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl,arylcarbonyl, arylthioalkyl, carboxy, carboxyalkyl, cyanoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl,heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,hydroxyalkyl, trialkylsilylalkyl, H₂NC(O)-alkyl, Z_(a)Z_(b)N—,Z_(a)Z_(b)Nalkyl, Z_(c)Z_(d)NC(O)— or Z_(c)Z_(d)NS(O)₂— wherein R_(xiv),R_(xv), R_(xvi), and R_(xvii) may occur at any open valence on compounds(xiv), (xv), (xvi) or (xvii);

Z_(a) and Z_(b) are each independently hydrogen, alkyl,alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, H₂NC(O)—,H₂NalkylC(O)—, H₂NC(O)-alkyl, dialkylNC(O)— or dialkylNC(O)-alkyl-;

Z_(c) and Z_(d) are each independently hydrogen, alkyl, alkoxyalkyl,aryl, arylalkyl, aryl(hydroxy)alkyl, cycloalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl,H₂NC(O)-alkyl-, dialkylNC(O)-alkyl-, dialkylN-alkyl-, or CHZ_(e)Z_(f);

Z_(e) is aryl or heteroaryl;

Z_(f) is heteroarylalkyl, heterocyclealkyl, or Z₁Z₂N-alkyl-;

m is 0, 1 or 2;

a is 0 or 1;

b is 0, 1, or 2;

c is 0, 1, 2 or 3; and

d is 0, 1, 2, 3 or 4.

Also provided are pharmaceutically acceptable compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically suitable carrier.

The object of the present invention is to provide compounds that areuseful for the preventive of or treatment of diseases caused by abnormalprotein kinase activity. In addition, the invention also providespharmaceutically effective compositions of the compounds of the presentinvention that are useful for the prevention of or treatment of saiddiseases.

The present invention also relates to a pharmaceutical composition whichcomprises at least one 5-substituted indazole compound of the formula(I) which may exist as a pharmaceutically acceptable salt or prodrugthereof, in the presence or absence of pharmaceutically acceptablecarriers, dragees, adjuvants or other auxiliary substances.

The compounds of the present invention have inhibitory activity againstGSK-3, ROCK-1, ROCK-2, JAK2, Cdc7 as well as other kinases and areuseful for the inhibition of such kinases. Certain compounds of thepresent invention are selective toward one or more kinases and may beuseful for the selective inhibition of such kinases. Accordingly, thecompounds of the present invention are useful as an active ingredientfor the preparation of a composition, which enables preventive and/ortherapeutic treatment of a disease caused by abnormal GSK-3 activity andmore particularly, of neurodegenerative diseases such as Alzheimer'sdisease. In addition, the compounds of the present invention are alsouseful as an active ingredient for the preparation of a composition forpreventive and/or therapeutic treatment of neurodegenerative diseasessuch as Parkinson's disease, tauopathies (e.g. frontotemporoparietaldementia, corticobasal degeneration, Pick's disease, progressivesupranuclear palsy) and other dementia including vascular dementia;acute stroke and other traumatic injuries; cerebrovascular accidents(e.g. age related macular degeneration); brain and spinal cord trauma;peripheral neuropathies; retinopathies and glaucoma; and other diseasessuch as non-insulin dependent diabetes (such as diabetes type II) andobesity; manic depressive illness; schizophrenia; alopecia; cancers suchas breast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia and several virus-induced tumors. Certain compounds ofthe present invention are useful as an active ingredient for thepreparation of a composition, which enables preventive and/ortherapeutic treatment of a disease caused by abnormal Cdc7 activity andmore particularly, cancer such as bladder cancer, breast cancer, coloncancer, kidney cancer, liver cancer, lung cancer, esophagus cancer,gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer,cervical cancer, thyroid cancer, prostate cancer, skin cancer, includingsquamous cell carcinoma, hematopoietic tumors of lymphoid lineage,including leukemia, acute lymphocytic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma, Burkitt's lymphoma,hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia, tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma, tumors of the central and peripheral nervous system,including astrocytoma, neuroblastoma, glioma and schwannomas, othertumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma,xeroderma pegmentosum, keratoxanthoma, thyroid follicular cancer andKaposi's sarcoma. In addition, the compounds of the present inventionare also useful as an active ingredient for the preparation of acomposition for preventive and/or therapeutic treatment of proliferativediseases such as benign prostate hyperplasia, familial adenomatosis,polyposis, neuro-fibromatosis, psoriasis, vascular smooth cellproliferation associated with atherosclerosis, pulmonary fibrosis,arthritis, glomerulonephritis, and post-surgical stenosis and restenosiscaused by abnormal Cdc7 activity.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the present invention have the formula (I) as describedabove. More particularly, compounds of formula (I) can include, but arenot limited to, compounds wherein A is (ii), (iii), (iv), (vii), (x),(xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), or(xxiii).

In another embodiment of the present invention there is disclosed acompound of formula (I), wherein A is (ii),

R₁ is hydrogen, alkoxyalkyl, alkyl, aryl, heteroaryl, heterocycle,R_(a)R_(b)N— or R_(c)R_(d)N—C(O)—; R₂ is hydrogen, alkoxycarbonyl,arylcarbonyl, heterocyclecarbonyl, alkylcarbonyl, orR_(e)R_(f)N-alkyl-C(O)—; R₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl,heterocycle, heterocyclealkyl, R_(j)R_(k)N—, or R_(j)R_(k)N-alkyl-; R₅is alkyl, aryl, or heteroaryl; R_(a) and R_(b) are each independentlyhydrogen, alkyl, arylalkyl, cycloalkylalkyl, heterocyclealkyl, R₄—C(O)—,or R₅—S(O)₂—; R_(c), and R_(d) are each independently hydrogen, alkyl,or heteroaryl, R_(e) and R_(f) are each independently hydrogen or alkyl,R_(j) and R_(k) are each independently hydrogen, alkyl, aryl, arylalkyl,cycloalkyl, or heterocycle; R_(ii) is alkyl, alkoxyalkyl,alkoxycarbonyl, aryl, arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl,arylcarbonyl, alkoxycarbonylalkyl, arylthioalkyl, carboxy, carboxyalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl,heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,hydroxyalkyl, trialkylsilylalkyl, Z_(a)Z_(b)N—, Z_(a)Z_(b)Nalkyl-, orZ_(c)Z_(d)NC(O)—; Z_(a) and Z_(b) are each independently hydrogen,alkyl, or H₂NalkylC(O)—; Z_(c) and Z_(d) are each independentlyhydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, ordialkylN-alkyl-; m is 0; and b is 0, 1, or 2.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (iii),

R₁ is hydrogen or R_(a)R_(b)N—; R₂ is hydrogen; R₄ isR_(j)R_(k)N-alkyl-; R_(a) and R_(b) are each independently hydrogen orR₄—C(O)—; R_(j) and R_(k) are each alkyl; R_(iii) isalkoxycarbonylalkyl, alkyl, arylalkyl, cyanoalkyl, heterocyclealkyl, orH₂NC(O)-alkyl-; c is 0, 1, or 2; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (iv),

R₁ is hydrogen or R_(a)R_(b)N—; R₂ is hydrogen; R_(a) and R_(b) are eachhydrogen; R_(iv) is aryl, arylalkyl, heterocycle, heterocyclealkyl,Z_(a)Z_(b)Nalkyl or Z_(c)Z_(d)NS(O)₂—; Z_(a) and Z_(b) are eachindependently hydrogen or alkyl; Z_(c) and Z_(d) are each alkyl; c is 0,1, or 2; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (vii),

R₁ is hydrogen, alkyl, or R_(a)R_(b)N; R₂ is hydrogen; R_(a) and R_(b)are each hydrogen; R_(vii) is alkyl, alkoxycarbonyl, aryl, arylalkyl,cycloalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, orZ_(c)Z_(d)NC(O)—; Z_(c) and Z_(d) are each independently hydrogen,alkyl, alkoxyalkyl, aryl, arylalkyl, aryl(hydroxy)alkyl, cycloalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl,hydroxyalkyl, or CHZ_(e)Z_(f); Z_(e) is aryl or heteroaryl, Z_(f) isheteroarylalkyl, heterocyclealkyl, or Z₁Z₂N-alkyl-; b is 1; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (x),

R₁ is hydrogen; R₂ is hydrogen; R_(x) is alkyl, aryl, Z_(a)Z_(b)N—, orZ_(c)Z_(d)NC(O)—; Z_(a) and Z_(b) are each independently hydrogen,alkyl, aryl, or arylalkyl; Z_(c) and Z_(d) are each independentlyhydrogen or arylalkyl; b is 1 or 2; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xiv),

R₁ is hydrogen; R₂ is hydrogen; R_(xiv) is Z_(a)Z_(b)N—; Z_(a) and Z_(b)are each independently hydrogen or cycloalkyl; c is 1; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xv),

R₁ is hydrogen or R_(a)R_(b)N—; R₂ is hydrogen; R_(a) and R_(b) are eachhydrogen; R_(xv) is Z_(a)Z_(b)N—; Z_(a) and Z_(b) are each independentlyhydrogen, alkoxycarbonylalkyl, aryl, arylalkyl, or cycloalkyl; d is 0 or1; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xvi),

R₁ is hydrogen; R₂ is hydrogen; R_(xvi) is Z_(a)Z_(b)N—; Z_(a) and Z_(b)are each independently hydrogen or cycloalkyl; d is 1; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xvii),

R₁ is hydrogen; R₂ is hydrogen; R_(xvii) is aryl or Z_(a)Z_(b)N—; Z_(a)and Z_(b) are each independently hydrogen, alkyl, alkoxycarbonylalkyl,aryl, arylalkyl, cycloalkyl, or H₂NC(O)-alkyl-; d is 0 or 1; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xviii),

R₁ is R_(a)R_(b)N—; R₂ is hydrogen; R_(a) and R_(b) are each hydrogen; cis 0; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xix),

R₁ is R_(a)R_(b)N—; R₂ is hydrogen; R_(a) and R_(b) are eachindependently hydrogen; c is 0; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xx),

R₁ is R_(a)R_(b)N—; R₂ is hydrogen; R₄ is R_(j)R_(k)N-alkyl-; R_(a) andR_(b) are each hydrogen or R₄—C(O)—; R_(j) and R_(k) are independentlyalkyl; R_(xx) is Z_(a)Z_(b)N— or heterocycle; Z_(a) and Z_(b) areindependently hydrogen or alkyl; c is 0 or 1; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xxi),

R₁ is R_(a)R_(b)N—; R₂ is hydrogen; R_(a) and R_(b) are each hydrogen;R_(xxi) is alkoxy; d is 1; and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xxii),

R₁ is R_(a)R_(b)N—; R₂ is hydrogen; R₄ is R_(j)R_(k)N-alkyl-; R_(a) andR_(b) are each independently hydrogen or R₄—C(O)—; R_(j) and R_(k) areeach alkyl; c is 0 and m is 0.

In another embodiment of the present invention, there is disclosed acompound of formula (I), wherein A is (xxiii),

R₁ is R_(a)R_(b)N—; R₂ is hydrogen; R_(a) and R_(b) are each hydrogen; cis 0; and m is 0.

Specific embodiments contemplated as part of the invention include, butare not limited to, compounds of formula (I), for example:

-   5-(1-benzyl-1H-1,2,3-triazol-5-yl)-1H-indazole compound with    5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole;-   5-(1H-1,2,3-triazol-5-yl)-1H-indazole;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole;-   5-[1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   2-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile;-   3-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile;-   4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile;-   5-{1-[2-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   5-{1-[3-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   5-{1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   5-{1-[3-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   5-{1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   5-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   methyl    3-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzoate;-   methyl    4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzoate;-   5-[1-(2,4-dimethylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(3,5-dimethylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(2,3-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(2,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-(3,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-{1-[2,4-bis(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   N-cyclohexyl-6-(1H-indazol-5-yl)imidazo[2,1-b][1,3]thiazol-5-amine;-   N-cyclohexyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-amine;-   N-cyclohexyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrazin-3-amine;-   5-[1-benzyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-1H-indazole;-   N-{3-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]propyl}-N,N-dimethylamine;-   N-cyclohexyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-amine;-   5-[4-(4-fluorophenyl)-1-(1-phenylethyl)-1H-imidazol-5-yl]-1H-indazole;-   2-(1H-indazol-5-yl)-N-isopropylimidazo[1,2-a]pyrimidin-3-amine;-   4-(1H-indazol-5-yl)-N-phenyl-1,3-thiazol-2-amine;-   5-(2-methyl-1,3-thiazol-4-yl)-1H-indazole;-   N-ethyl-4-(1H-indazol-5-yl)-1,3-thiazol-2-amine;-   N-benzyl-4-(1H-indazol-5-yl)-1,3-thiazol-2-amine;-   4-(1H-indazol-5-yl)-1,3-thiazol-2-amine;-   4-(1H-indazol-5-yl)-N-(2-phenylethyl)-1,3-thiazol-2-amine;-   N-benzyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-amine;-   N-butyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-amine;-   N-(4-chlorophenyl)-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-amine;-   2-(1H-indazol-5-yl)-N-(4-methoxyphenyl)imidazo[1,2-a]pyrimidin-3-amine;-   2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidine;-   methyl N-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl]glycinate;-   N-benzyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-amine;-   N-(4-chlorophenyl)-2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-amine;-   2-(1H-indazol-5-yl)-N-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-amine;-   tert-butyl    4-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]piperidine-1-carboxylate;-   3,5-bis(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-phenyl-1H-indazole;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-4-yl)carbonyl]-1H-indazol-3-amine;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-methoxyacetamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]butanamide;-   5-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]-1H-indazole;-   5-{4-(4-fluorophenyl)-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1H-imidazol-5-yl}-1H-indazole;-   5-{4-(4-fluorophenyl)-1-[3-(4-methylpiperazin-1-yl)propyl]-1H-imidazol-5-yl}-1H-indazole;-   ethyl 5-(1H-indazol-5-yl)isoxazole-3-carboxylate;-   5-(1H-indazol-5-yl)-N-methylisoxazole-3-carboxamide;-   5-(3-benzylisoxazol-5-yl)-1H-indazole;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide;-   5-(3-propylisoxazol-5-yl)-1H-indazole;-   N-benzyl-4-(1H-indazol-5-yl)-5-phenyl-1,3-thiazol-2-amine;-   4-(1H-indazol-5-yl)-N,5-diphenyl-1,3-thiazol-2-amine;-   5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazole;-   5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl)-1H-indazole;-   2-(1H-indazol-5-yl)-3-phenylimidazo[1,2-a]pyrimidine;-   5-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[3-(piperidin-1-ylcarbonyl)isoxazol-5-yl]-1H-indazole;-   5-(1H-indazol-5-yl)-N-phenylisoxazole-3-carboxamide;-   N-cyclohexyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-[3-(piperidin-1-ylmethyl)isoxazol-5-yl]-1H-indazole;-   [5-(1H-indazol-5-yl)isoxazol-3-yl]methanol;-   5-(1H-indazol-5-yl)-N-(2-methoxyethyl)isoxazole-3-carboxamide;-   5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazole;-   5-(4-benzyl-1H-1,2,3-triazol-1-yl)-1H-indazole;-   5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl)-1H-indazol-3-amine;-   5-(3-isobutylisoxazol-5-yl)-1H-indazol-3-amine;-   5-(3-benzylisoxazol-5-yl)-1H-indazol-3-amine;-   N-{2-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]ethyl}-N,N-dimethylamine;-   5-[4-(4-fluorophenyl)-1-(3-morpholin-4-ylpropyl)-1H-imidazol-5-yl]-1H-indazole;-   5-[4-(4-fluorophenyl)-1-(3-pyrrolidin-1-ylpropyl)-1H-imidazol-5-yl]-1H-indazole;-   5-{4-(4-fluorophenyl)-1-[2-(4-methylpiperidin-1-yl)ethyl]-1H-imidazol-5-yl}-1H-indazole;-   5-[1-(1-benzylpiperidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-1H-indazole;-   5-[4-(4-fluorophenyl)-1-(2-morpholin-4-ylethyl)-1H-imidazol-5-yl]-1H-indazole;-   5-[1-(1-benzylpyrrolidin-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-1H-indazole;-   2-{4-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]piperidin-1-yl}-2-oxoethanol;-   5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-2-ol;-   5-[4-(methoxymethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;-   1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]-1-phenylethanol;-   5-(4-propyl-1H-1,2,3-triazol-1-yl)-1H-indazole;-   1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-2-ol;-   3-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-1-ol;-   1-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-1,2,3-benzotriazole;-   5-{4-[(phenylthio)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole;-   5-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1H-indazole;-   5-[4-(2-phenylethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;-   5-[4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;-   5-(4-cyclopentyl-1H-1,2,3-triazol-1-yl)-1H-indazole;-   1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]cyclohexanol;-   5-[4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;-   5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole;-   5-[4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;-   [1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](phenyl)methanone;-   N,N-diethyl-N-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}amine;-   ethyl    N-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]-beta-alaninate;-   5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazole;-   5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   N³-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]-β-alaninamide;-   5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   N-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}-N′-(3-methylphenyl)urea;-   5-(1H-indazol-5-yl)-N-(2-isopropoxyethyl)isoxazole-3-carboxamide;-   5-[3-(morpholin-4-ylcarbonyl)isoxazol-5-yl]-1H-indazole;-   5-(1H-indazol-5-yl)-N-(3-morpholin-4-ylpropyl)isoxazole-3-carboxamide;-   N-[2-(1H-imidazol-4-yl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   (3R)-1-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperidin-3-ol;-   1-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperidine-3-carboxamide;-   2-[2-(4-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperazin-1-yl)ethoxy]ethanol;-   5-{3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole;-   N-(3-hydroxypropyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[(1R)-2-hydroxy-1-phenylethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[3-(1H-imidazol-1-yl)propyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[3-(2-oxopyrrolidin-1-yl)propyl]isoxazole-3-carboxamide;-   N-{2-[4-(aminosulfonyl)phenyl]ethyl}-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   [1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](3-chlorophenyl)methanone;-   [1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](cyclopropyl)methanone;-   5-[5-cyclopropyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   N¹-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]methyl}glycinamide;-   (4-fluorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;-   (4-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;-   (3-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;-   (2-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;-   cyclopentyl[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;-   1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid;-   5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;-   5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   [4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl](tetrahydro-2H-pyran-4-yl)methanone;-   5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-{1-benzyl-5-[(4-methylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-ol;-   1-acetyl-5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   1-benzyl-4-(1H-indazol-5-yl)-N,N-dimethyl-1H-1,2,3-triazole-5-carboxamide;-   N,1-dibenzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   N-(2-hydroxy-2-phenylethyl)-5-(1H-indazol-5-yl)-N-methylisoxazole-3-carboxamide;-   N-[(1S)-2-hydroxy-1-phenylethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-benzyl-N-(2-hydroxyethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-3-methyl-1H-indazole;-   5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   2-{2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]ethyl}-1H-isoindole-1,3(2H)-dione;-   5-{4-[(2,4-dichlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole;-   5-{4-[(2,6-dichlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole;-   5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   1-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indazole;-   5-[1-benzyl-5-(piperidin-1-ylcarbonyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   5-[1-benzyl-5-(morpholin-4-ylcarbonyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;-   5-[1-benzyl-5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   N-[(1S)-1-benzyl-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-{3-[(3-phenylmorpholin-4-yl)carbonyl]isoxazol-5-yl}-1H-indazole;-   N-benzyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   ((1S)-2-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol;-   N-[(1R)-3-hydroxy-1-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[(1S)-3-hydroxy-1-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-2,3-dihydro-1H-inden-1-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-2,3-dihydro-1H-inden-2-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(1-phenylpropyl)isoxazole-3-carboxamide;-   5-{1-benzyl-5-[3-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;-   5-{1-benzyl-5-[4-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;-   N-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}acetamide;-   N-{4-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}acetamide;-   5-{1-benzyl-5-[3-(1H-pyrazol-1-yl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;-   5-[1-benzyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]-N-phenylbenzamide;-   3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]-N-benzylbenzamide;-   5-[1-benzyl-5-(1-methyl-1H-indol-5-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   5-[1-benzyl-5-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   5-[1-benzyl-5-(3-morpholin-4-ylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   5-[3-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)isoxazol-5-yl]-1H-indazole;-   5-{3-[(4-methyl-2-phenylpiperazin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole;-   1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-amine;-   N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide;-   N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzenesulfonamide;-   N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-(4-methoxyphenyl)urea;-   N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]butanamide;-   N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-methylpropanamide;-   N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]cyclopropanecarboxamide;-   N-[1-benzoyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-fluorobenzamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide;-   N-benzyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   N-[(1R)-1-benzyl-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazole;-   N-[(1R)-3-hydroxy-1-phenylpropyl]-5-(3-methyl-1H-indazol-5-yl)isoxazole-3-carboxamide;-   3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenol;-   3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]benzamide;-   5-{1-benzyl-5-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-chlorobenzamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-4-chlorobenzamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]ethanesulfonamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzenesulfonamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-chlorobenzenesulfonamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-chlorobenzenesulfonamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-4-chlorobenzenesulfonamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2,5-dimethylfuran-3-sulfonamide;-   5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-(2-chlorobenzyl)-1H-indazol-3-amine;-   5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-(3-chlorobenzyl)-1H-indazol-3-amine;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-chlorobenzamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-furamide;-   5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-ethyl-1H-indazol-3-amine;-   5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-(4-chlorobenzyl)-1H-indazol-3-amine;-   5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-(3-furylmethyl)-1H-indazol-3-amine;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-[5-methyl-2-(trifluoromethyl)-3-furyl]urea;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-furamide;-   5-(1H-indazol-5-yl)-N-[(1S)-1-phenylpropyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1R)-1-phenylpropyl]isoxazole-3-carboxamide;-   5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-amine;-   1-benzyl-4-(1H-indazol-5-yl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-4-(1H-indazol-5-yl)-N-(2-isopropoxyethyl)-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-4-(1H-indazol-5-yl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-4-(1H-indazol-5-yl)-N-(tetrahydrofuran-3-ylmethyl)-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-cyclopentyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-(cyclopentylmethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-ethyl-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-4-(1H-indazol-5-yl)-N-isopropyl-N-methyl-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-4-(1H-indazol-5-yl)-N-(2-methoxyethyl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-4-(1H-indazol-5-yl)-N-phenyl-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-(4-chlorophenyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-4-(1H-indazol-5-yl)-N-(2-morpholin-4-ylethyl)-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-[2-(dimethylamino)ethyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-(2-hydroxyethyl)-4-(1H-indazol-5-yl)-N-propyl-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-[3-(dimethylamino)propyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-[2-(diethylamino)ethyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;-   N,1-dibenzyl-N-ethyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   N,1-dibenzyl-N-(2-hydroxyethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   (3R)-1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-3-ol;-   1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidine-4-carboxamide;-   5-{1-benzyl-5-[(2,6-dimethylmorpholin-4-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   5-{5-[(4-acetylpiperazin-1-yl)carbonyl]-1-benzyl-1H-1,2,3-triazol-4-yl}-1H-indazole;-   5-{1-benzyl-5-[(4-phenylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;-   1-benzyl-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   1-benzyl-N-[3-(1H-imidazol-1-yl)propyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-ethylurea;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-phenylurea;-   N-benzyl-N′-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]urea;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-(2-chlorophenyl)urea;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-(3-chlorophenyl)urea;-   N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-(4-chlorophenyl)urea;-   N-[5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide;-   3-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanenitrile;-   2-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]acetamide;-   methyl 3-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanoate;-   3-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanamide;-   [4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]acetonitrile;-   4-(3-amino-1H-indazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide;-   5-pyrazin-2-yl-1H-indazol-3-amine;-   5-thien-2-yl-1H-indazol-3-amine;-   5-(2-aminopyrimidin-4-yl)-1H-indazol-3-amine;-   5-(2-methoxypyridin-3-yl)-1H-indazol-3-amine;-   5-imidazo[1,2-a]pyridin-3-yl-1H-indazol-3-amine;-   N²,N²-dimethyl-N¹-[5-(1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]glycinamide;-   5-(1H-pyrazol-5-yl)-1H-indazol-3-amine;-   5-(4-methyl-1H-imidazol-5-yl)-1H-indazol-3-amine;-   5-(1H-imidazol-4-yl)-1H-indazol-3-amine;-   N²,N²-dimethyl-N¹-{5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}glycinamide;-   5-(1-benzyl-1H-imidazol-4-yl)-1H-indazol-3-amine;-   N¹-{5-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}-N²,N²-dimethylglycinamide;-   N²,N²-dimethyl-N¹-{5-[1-(2-piperidin-1-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}glycinamide;-   N²,N²-dimethyl-N¹-{5-[1-(2-morpholin-4-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}glycinamide;-   N¹-(5-{1-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-yl)-N²,N²-dimethylglycinamide;-   N¹-(5-{1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-yl)-N²,N²-dimethylglycinamide;-   2-(4-{3-[(N,N-dimethylglycyl)amino]-1H-indazol-5-yl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic    acid;-   ethyl    (4-{3-[(N,N-dimethylglycyl)amino]-1H-indazol-5-yl}-1H-1,2,3-triazol-1-yl)acetate;-   N²,N²-dimethyl-N¹-(5-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-yl)glycinamide;-   N¹-[5-(3-furyl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide;-   N²,N²-dimethyl-N¹-[5-(1H-pyrazol-5-yl)-1H-indazol-3-yl]glycinamide;-   N²,N²-dimethyl-N¹-(5-pyrimidin-5-yl-1H-indazol-3-yl)glycinamide;-   N¹-[5-(2,1,3-benzoxadiazol-5-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide;-   N²,N²-dimethyl-N¹-[5-(1H-pyrazol-4-yl)-1H-indazol-3-yl]glycinamide;-   N²,N²-dimethyl-N¹-[5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]glycinamide;-   N¹-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide;-   N¹-{5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indazol-3-yl}-N²,N²-dimethylglycinamide;-   N²,N²-dimethyl-N¹-[5-(2-morpholin-4-ylpyrimidin-5-yl)-1H-indazol-3-yl]glycinamide;-   N²,N²-dimethyl-N¹-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]-1H-indazol-3-yl}glycinamide;-   N¹-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide;-   N¹-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-methylglycinamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-pyrrolidin-1-ylacetamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-cyclopentylglycinamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-cyclopropylglycinamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-tetrahydro-2H-pyran-4-yl)glycinamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-(3-hydroxypyrrolidin-1-yl)acetamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-(3-hydroxypiperidin-1-yl)acetamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N³,N³-dimethyl-beta-alaninamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-morpholin-4-ylacetamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-(3-oxopiperazin-1-yl)acetamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-isopropylglycinamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-cyclohexylglycinamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]acetamide;-   N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-cyclobutylglycinamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-propylurea;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]ethanesulfonamide;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(cyclopropylmethyl)-1H-indazol-3-amine;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-ethylurea;-   1-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]pyrrolidin-2-one;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-4-(dimethylamino)butanamide;-   N-3,4-dihydro-1H-isochromen-4-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-(cyclohexylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-(3-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(2-methoxybenzyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[2-(trifluoromethyl)benzyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[3-(trifluoromethyl)benzyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[4-(trifluoromethyl)benzyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(pyridin-2-ylmethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(pyridin-3-ylmethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(pyridin-4-ylmethyl)isoxazole-3-carboxamide;-   N-(2-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-(4-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(1-phenyl-2-piperidin-1-ylethyl)isoxazole-3-carboxamide;-   N-[2-(1H-imidazol-1-yl)-1-phenylethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(2-morpholin-4-yl-1-phenylethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[2-(4-methylpiperazin-1-yl)-1-phenylethyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(1-phenyl-2-pyrrolidin-1-ylethyl)isoxazole-3-carboxamide;-   tert-butyl    2-({[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}amino)-2-phenylethylcarbamate;-   5-(1H-indazol-5-yl)-N-(1-naphthylmethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(2-phenylethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(2-pyridin-2-ylethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(2-pyridin-3-ylethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-(2-pyridin-4-ylethyl)isoxazole-3-carboxamide;-   N-[2-(2-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[2-(3-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[2-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-benzyl-N-ethyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-methyl-N-(1-naphthylmethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-methyl-N-(2-phenylethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-methyl-N-(2-pyridin-2-ylethyl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1R)-1-phenylethyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-1,2,3,4-tetrahydronaphthalen-1-ylisoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1S)-1-(1-naphthyl)ethyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1R)-1-(1-naphthyl)ethyl]isoxazole-3-carboxamide;-   N-[3-(dimethylamino)-1-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-(3,4-dihydro-2H-1,5-benzodioxepin-6-ylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1-methyl-1H-indol-4-yl)methyl]isoxazole-3-carboxamide;-   5-{3-[(3-phenylpyrrolidin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole;-   5-{3-[(2-phenylpyrrolidin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole;-   5-{3-[(2-phenylpiperidin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole;-   5-(1H-indazol-5-yl)-N-[(1S)-1-phenylethyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1R)-1-(4-methylphenyl)ethyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1S)-1-(4-methylphenyl)ethyl]isoxazole-3-carboxamide;-   N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[(1R)-1-(4-bromophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[(1S)-1-(4-bromophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[(1R)-1-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[(1S)-1-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1S)-1-(2-naphthyl)ethyl]isoxazole-3-carboxamide;-   N-[1-(4-ethoxyphenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[2-hydroxy-1-(4-isopropylphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[1-(3,4-dimethylphenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[2-hydroxy-1-(2-methoxyphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[2-hydroxy-1-(4-methylphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1R)-1-(2-methoxyphenyl)ethyl]isoxazole-3-carboxamide;-   N-[(1S)-1-(3,4-difluorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]isoxazole-3-carboxamide;-   5-(1H-indazol-5-yl)-N-{(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}    isoxazole-3-carboxamide;-   N-[1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   N-[1-(3,5-dichlorophenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;-   tert-butyl    5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-2-yl)carbonyl]-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-[(dimethylamino)acetyl]-1H-indazol-3-amine;-   tert-butyl    3-amino-5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole-1-carboxylate;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-piperidin-1-ylacetamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-morpholin-4-ylacetamide;-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-1-methylpiperidine-2-carboxamide;-   2-(1H-indazol-5-yl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]-1,3-thiazole-5-carboxamide-   N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-fluorobenzamide;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N,N-dimethyl-1H-indazole-3-carboxamide;-   methyl 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole-3-carboxylate;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-(1-methyl-1H-imidazol-2-yl)-1H-indazole;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-morpholin-4-yl-1H-indazole;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-(4-methylpiperazin-1-yl)-1H-indazole;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-thien-2-yl-1H-indazole;-   5-(1-benzyl-5-cyclohexyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   5-[1-benzyl-5-(cyclohexylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-(1,3-thiazol-2-yl)-1H-indazole;-   5-(1,5-dibenzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   5-(1-benzyl-5-thien-2-yl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(2-morpholin-4-ylethyl)-1H-indazol-3-amine;-   5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-3-methyl-1H-indazole;-   5-[1-benzyl-5-(cyclopentylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-butyl-1H-indazol-3-amine;-   N-benzyl-5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(4-chlorobenzyl)-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(4-methoxybenzyl)-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(3-fluorobenzyl)-1H-indazol-3-amine;-   4-({[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]amino}methyl)benzonitrile;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(2,4-difluorobenzyl)-1H-indazol-3-amine;-   5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(cyclohexylmethyl)-1H-indazol-3-amine;    and-   5-(1-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazole.

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkoxyalkyl” as used herein, means an alkoxyalkoxygroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkoxyalkoxyalkyl include, but are not limited to,tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl,and 2-(2-methoxyethoxy)ethyl.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkoxycarbonylalkyl include, but are not limited to,3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and2-tert-butoxycarbonylethyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkylcarbonylalkyl include, but are not limited to, 2-oxopropyl,3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 1 to 10 carbon atoms. Representativeexamples of alkylene include, but are not limited to, —CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkylene-NR_(g)—” as used herein, means an alkylene group, asdefined herein, appended to the parent molecular moiety through a—NR_(g)— group, as defined herein.

The term “alkylsulfinyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfinyl group, as defined herein. Representative examples ofalkylsulfinyl include, but are not limited to, methylsulfinyl andethylsulfinyl.

The term “alkylsulfinylalkyl” as used herein, means an alkylsulfinylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyland ethylsulfinylmethyl.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylsulfonylalkyl” as used herein, means an alkylsulfonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyland ethylsulfonylmethyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited to,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkylthioalkyl” as used herein, means an alkylthio group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples ofalkylthioalkyl include, but are not limited to, methylthiomethyl and2-(ethylthio)ethyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl,” as used herein, means phenyl, a bicyclic aryl or atricyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to acycloalkyl, or a phenyl fused to a cycloalkenyl, or a phenyl fused to amonocyclic heteroaryl ring as defined herein, or a phenyl fused to amonocyclic heterocycle as defined herein. The bicyclic aryl of thepresent invention must be attached to the parent molecular moietythrough any available carbon atom contained within the phenyl ring.Representative examples of the bicyclic aryl include, but are notlimited to, 2,3-dihydro-1,4-benzodioxin-5-yl,2,3-dihydro-1,4-benzodioxin-6-yl, 3,4-dihydro-2H-1,5-benzodioxepin-6-yl,dihydroindenyl, indenyl, indol-4-yl, naphthyl, dihydronaphthalenyl, andtetrahydronaphthalenyl. The tricyclic aryl is anthracene orphenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a bicyclicaryl fused to a cycloalkenyl, or a bicyclic aryl fused to a phenyl. Thetricyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the tricyclic aryl. Representative examplesof tricyclic aryl ring include, but are not limited to, azulenyl,dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.

The aryl groups of this invention are optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, aryl*NC(O)—,aryl*NHC(O)NH—, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl,formylalkyl, halogen, haloalkyl, heteroaryl, hydroxy, hydroxyalkyl,mercapto, morpholino, nitro, Z₁Z₂N—, or (Z₃Z₄N)carbonyl. Aryl* isoptionally substituted with 1, 2 or 3 substituents independentlyselected from alkyl, halo, cyano or nitro. Z₁ and Z₂ are eachindependently selected from hydrogen, alkyl or alkylcarbonyl.

The term “aryloxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of aryloxy include, but are not limited to,phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy,and 3,5-dimethoxyphenoxy.

The term “aryloxyalkyl” as used herein, means an aryloxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of aryloxyalkylinclude, but are not limited to, 2-phenoxyethyl, 3-naphth-2-yloxypropyland 3-bromophenoxymethyl.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “aryl(hydroxy)alkyl” as used herein, means an aryl group, asdefined herein, appended to the parent molecular moiety through analkylene group bearing one hydroxy group, as defined herein.Representative examples of aryl(hydroxy)alkyl include, but are notlimited to, 2-phenylethanol-2-yl and 2-hydroxy-2-phenylethanyl.

The term “arylcarbonyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of arylcarbonylinclude, but are not limited to, benzoyl and naphthoyl.

The term “arylthio” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of arylthio include, but are not limited to,phenylthio and 2-naphthylthio.

The term “arylthioalkyl” as used herein, means an arylthio group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples ofarylthioalkyl include, but are not limited to, phenylthiomethyl,2-naphth-2-ylthioethyl, and 5-phenylthiomethyl.

The term “azido” as used herein, means a —N₃ group.

The term “azidoalkyl” as used herein, means an azido group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “carboxyalkyl” as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples ofcarboxyalkyl include, but are not limited to, carboxymethyl,2-carboxyethyl, and 3-carboxypropyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl” as used herein, means a monocyclic or bicyclicring system containing from 3 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of monocyclic ring systems include, but are notlimited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yland 3-cyclopenten-1-yl. Bicyclic ring systems are exemplified by amonocyclic cycloalkenyl ring system which is fused to another monocycliccycloalkyl ring as defined herein, a monocyclic aryl ring as definedherein, a monocyclic heterocycle as defined herein or a monocyclicheteroaryl as defined herein. The bicyclic ring systems of the presentinvention must be appended to the parent molecular moiety through anavailable carbon atom within the cycloalkenyl ring. Representativeexamples of bicyclic ring systems include, but are not limited to,4,5-dihydro-benzo[1,2,5]oxadiazole, 3a,4,5,6,7,7a-hexahydro-1H-indenyl,1,2,3,4,5,6-hexahydro-pentalenyl,1,2,3,4,4a,5,6,8a-octahydro-pentalenyl.

The term “cycloalkyl” as used herein, means a monocyclic, bicyclic, orspirocyclic ring system. Monocyclic ring systems are exemplified by asaturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicycliccycloalkyl groups of the present invention are exemplified by amonocyclic cycloalkyl ring fused to another monocyclic cycloalkyl ring,or a monocyclic cycloalkyl ring fused cycloalkenyl, or a monocycliccycloalkyl ring fused to a phenyl ring, or a monocyclic cycloalkyl ringfused to a monocyclic heteroaryl ring as defined herein, or a monocycliccycloalkyl ring fused to a monocyclic heterocycle as defined herein. Thebicyclic cycloalkyl ring systems of the present invention must beappended to the parent molecular moiety through an available carbon atomwithin the monocycloalkyl ring.

The cycloalkyl groups of the present invention are optionallysubstituted with 1, 2, 3, or 4 substituents selected from alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio,alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, mercapto, oxo, Z₁Z₂N—, or(Z₃Z₄N)carbonyl.

The term “cycloalkylalkyl,” as used herein, means a cycloalkyl groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “cycloalkylcarbonyl” as used herein, means cycloalkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,2-cyclobutylcarbonyl, and cyclohexylcarbonyl.

The term “formyl” as used herein, means a —C(O)H group.

The term “formylalkyl” as used herein, means a formyl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of formylalkylinclude, but are not limited to, formylmethyl and 2-formylethyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples of haloalkylinclude, but are not limited to, chloromethyl, 2-fluoroethyl,trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 memberedring containing at least one heteroatom independently selected from O,N, or S. The 5 membered ring contains two double bonds may contain one,two, three or four heteroatoms. The 6 membered ring contains threedouble bonds may contain one, two, three or four heteroatoms. The 5 or 6membered heteroaryl is connected to the parent molecular moiety throughany carbon atom or any nitrogen atom contained within the heteroaryl.Representative examples of monocyclic heteroaryl include, but are notlimited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, andtriazinyl. The bicyclic heteroaryl consists of a monocyclic heteroarylfused to a monocyclic aryl ring as defined herein, a monocycliccycloalkyl ring as defined herein, a monocyclic cycloalkenyl ring asdefined herein, another monocyclic heteroaryl or a monocyclicheterocycle ring as defined herein. The bicyclic heteroaryl ring systemsof the present invention must be appended to the parent molecular moietythrough an available carbon atom within the heteroaryl ring. Thebicyclic heteroaryl is connected to the parent molecular moiety throughany carbon atom or any nitrogen atom contained within the bicyclicheteroaryl. Representative examples of bicyclic heteroaryl include, butare not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl,benzimidazolyl, benzodioxolyl, benzothiophenyl, chromenyl, cinnolinyl,furopyridine, indolyl, indazolyl, isoindolyl, isoquinolinyl,naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridine andthienopyridinyl.

The heteroaryl groups of the present invention are optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl,alkynyl, benzyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,Z₁Z₂N—, or (Z₃Z₄N)carbonyl. Heteroaryl groups of the present inventionthat are substituted may be present as tautomers. The present inventionencompasses all tautomers including non-aromatic tautomers.

The term “heteroarylalkyl,” as used herein, means a heteroaryl groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “heterocycle” or “heterocyclic” as used herein, refers to amonocyclic, bicyclic, tricyclic or a spirocyclic ring system thatcontains at least one heteroatom. The monocyclic heterocycle is a 3, 4,5, 6 or 7 membered ring containing at least one heteroatom independentlyselected from the group consisting of O, N, and S. The 3 or 4 memberedring contains 1 heteroatom selected from the group consisting of O, Nand S. The 5 membered ring contains zero or one double bond and one, twoor three heteroatoms selected from the group consisting of O, N and S.The 6 or 7 membered ring contains zero, one or two double bonds and one,two or three heteroatoms selected from the group consisting of O, N andS. The monocyclic heterocycle is connected to the parent molecularmoiety through any carbon atom or any nitrogen atom contained within themonocyclic heterocycle. Representative examples of monocyclicheterocycle include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, isoindoline-1,3-dione,morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone),thiopyranyl, and trithianyl. The bicyclic heterocycle of the presentinvention is defined as a monocyclic heterocycle fused to a phenylgroup, a cycloalkyl group as defined herein, a cycloalkenyl group asdefined herein, another monocyclic heterocycle group as defined herein,or a spirocyclic ring wherein one carbon atom of the monocyclicheterocycle is bridged by two ends of an alkylene chain. The bicyclicheterocycle of the present invention is connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the heterocyclic ring. Representative examples of bicyclicheterocycle include, but are not limited to, 1,3-benzodioxolyl,1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl,2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl,3,4-dihydro-1H-isochromen-4-yl, 2,3-dihydro-1H-indolyl, succinmimidyl,and 1,2,3,4-tetrahydroquinolinyl. The tricyclic heterocycle is abicyclic heterocycle fused to a phenyl, or a bicyclic heterocycle fusedto a cycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or abicyclic heterocycle fused to a monocyclic heterocycle. The tricyclicheterocycle is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the tricyclicheterocycle. Representative examples of tricyclic heterocycle include,but are not limited to, 2,3,4,4a,9,9a-hexahydro-1H-carbazolyl,5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.

The heterocycles of this invention are optionally substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl, benzyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, hydroxyalkylcarbonyl,hydroxyalkoxyalkyl, mercapto, oxo, Z₁Z₂N—, or (Z₃Z₄N)carbonyl.

The term “heterocyclealkyl,” as used herein, means a heterocycle groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “heterocyclecarbonyl” as used herein, means a heterocycle, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “hydroxyalkylcarbonyl” as used herein, means a hydroxyalkylgroup, as defined herein, as appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examplesinclude, but are not limited to, 2-hydroxyacetyl, and 4-hydroxybutanoyl.

The term “hydroxyalkoxyalkyl” as used herein, means a hydroxyalkoxygroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkoxyalkyl include, but are not limited to,(2-hydroxy-ethoxy)-ethyl, and (3-hydroxyl-propoxyl)-ethyl.

The term “hydroxy-protecting group” or “O-protecting group” means asubstituent that protects hydroxyl groups against undesirable reactionsduring synthetic procedures. Examples of hydroxy-protecting groupsinclude, but are not limited to, substituted methyl ethers, for example,methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl;tetrahydropyranyl ethers; substituted ethyl ethers, for example,2,2,2-trichloroethyl and t-butyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclicacetals and ketals, for example, methylene acetal, acetonide andbenzylidene acetal; cyclic ortho esters, for example, methoxymethylene;cyclic carbonates; and cyclic boronates. Commonly usedhydroxy-protecting groups are disclosed in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, New York (1999).

The term “mercapto” as used herein, means a —SH group.

The term “nitrogen protecting group” as used herein, means those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Preferred nitrogen protecting groups are acetyl,benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl,tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, andtriphenylmethyl (trityl).

The term “nitro” as used herein, means a —NO₂ group.

The term “trialkylsilyl” as used herein, means three independentlyselected alkyl groups, as defined herein, appended to the parentmolecular moiety through a silicon atom. Representative examples oftrialkylsilyl include, but are not limited to, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl and triisopropylsilyl.

The term “trialkylsilylalkyl” as used herein, means a trialkylsilylgroup, as defined herein, appended to the parent molecular through analkylene group, as defined herein. Representative examples oftrialkylsilylalkyl include, but are not limited to,trimethylsilylmethyl, 2-trimethylsilylethyl, and2-t-butyldimethylsilylethyl.

The term “Z₁Z₂N” as used herein, means two groups, Z₁ and Z₂, which areappended to the parent molecular moiety through a nitrogen atom. Z₁ andZ₂ are each independently hydrogen, alkoxycarbonyl, alkyl,alkylcarbonyl, aryl, arylalkyl and formyl. In certain instances withinthe present invention, Z₁ and Z₂ taken together with the nitrogen atomto which they are attached form a heterocyclic ring. Representativeexamples of Z₁Z₂N include, but are not limited to, amino, methylamino,acetylamino, acetylmethylamino, phenylamino, benzylamino, azetidinyl,pyrrolidinyl and piperidinyl.

The term “Z₃Z₄N” as used herein, means two groups, Z₃ and Z₄, which areappended to the parent molecular moiety through a nitrogen atom. Z₃ andZ₄ are each independently hydrogen, alkyl, aryl and arylalkyl.Representative examples of Z₃Z₄N include, but are not limited to, amino,methylamino, phenylamino and benzylamino.

The term “(Z₃Z₄N)carbonyl” as used herein, means a NZ₃Z₄ group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of(Z₃Z₄N)carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “oxo” as used herein, means a ═O moiety.

The term “sulfinyl” as used herein, means a —S(O)— group.

The term “sulfonyl” as used herein, means a —SO₂— group.

The term “sulfonamide” as used herein means a —SO₂NH₂ group.

The term “tautomer” as used herein means a proton shift from one atom ofa compound to another atom of the same compound wherein two or morestructurally distinct compounds are in equilibrium with each other.

Compounds of the present invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The presentinvention contemplates various stereoisomers and mixtures thereof andthese are specifically included within the scope of this invention.Stereoisomers include enantiomers and diastereomers, and mixtures ofenantiomers or diastereomers. Individual stereoisomers of compounds ofthe present invention may be prepared synthetically from commerciallyavailable starting materials that contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution which iswell known to those of ordinary skill in the art. These methods ofresolution are exemplified by (1) attachment of a mixture of enantiomersto a chiral auxiliary, separation of the resulting mixture ofdiastereomers by recrystallization or chromatography and liberation ofthe optically pure product from the auxiliary; or (2) direct separationof the mixture of optical enantiomers on chiral chromatographic columns.

The compounds and processes of the present invention will be betterunderstood by reference to the following Examples, which are intended asan illustration of and not a limitation upon the scope of the invention.Further, all citations herein are incorporated by reference.

Compound names are assigned by using Name Pro naming software, which isprovided by ACD/Labs. Alternatively, compound names are assigned usingAUTONOM naming software, which is provided by MDL Information SystemsGmbH (formerly known as Beilstein Informationssysteme) of Frankfurt,Germany, and is part of the CHEMDRAW® ULTRA v. 6.0.2 software suite andISIS Draw v. 2.5. Also, compound names are assigned using Struct=Namenaming algorithm, which is part of the CHEMDRAW® ULTRA v. 9.0.7 softwaresuite.

Abbreviations

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: DMF for N,N-dimethylformamide, DMSOfor dimethyl sulfoxide, EtOAc for ethyl acetate, CHCl₃ for chloroform,CH₂Cl₂ for dichloromethane, CH₃CN for acetonitrile, THF fortetrahydrofuran, HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, EDC or EDCI for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, LC/MS forliquid chromatography/mass spectroscopy, NH₄OAc for ammonium acetate,NaBH(OAc)₃ for sodium triacetoxyborohydride, PBS for phosphate bufferedsaline, TMS for trimethylsilyl, MW for microwave, DMAP for4-(dimethylamino)pyridine, dppf for1,1′-bis(diphenylphosphino)ferrocene, TFA for trifluoroacetic acid,BINAP for 2,2′-bis(diphenylphosphino)-1,1′-binaphyl, TBAF fortetrabutylammonium fluoride, Tween for polyoxoethylenesorbitanmonolaurate HPLC for high pressure liquid chromatography, DME for1,2-dimethoxyethane, Boc for tert-butoxycarbonyl, BSA for bovine serumalbumin, DTT for dithiothreitol, ATP for adenosine triphosphate, EDTAfor ethylenediaminetetraacetic acid, HPMC forhydroxypropylmethylcellulose, TMB for 3,3′,5,5′-tetramethylbenzidine andHEPES for 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid.

PREPARATION OF COMPOUNDS OF THE PRESENT INVENTION

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic Schemes andExamples that illustrate a means by which the compounds of the presentinvention can be prepared.

As shown in Scheme 1, compounds of formula 2 which are representative ofcompounds of formula (I), may be made accordingly. Compounds of formula1, wherein R₁ and R₂ are as defined in formula (I), and X₁ is iodo,bromo or chloro, and which may be obtained from commercial sources ormay be synthesized according to methods known in the literature, whentreated with reagent A-M₁, wherein A is defined in formula (I) and M₁ is—Sn(R_(z))₃ or —B(OR_(y))₂, wherein R_(z) is alkyl or aryl, and R_(y) ishydrogen, alkyl, aryl or the two R_(y) groups together with the boronatom to which they are attached form a 1,3-dioxoborolane, in thepresence of a palladium catalyst will provide compounds of formula 2.Such reactions between compounds of formula 1 and compounds of formulaA-Sn(R_(z))₃, commonly known as Stille couplings, utilize a palladiumcatalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),tris(dibenzylidineacetone)dipalladium or palladium diacetate, in thepresence or absence of a ligand such as tri(2-furyl)phosphine ortriphenylarsine in a solvent such as toluene or DMF at a temperaturefrom about 25° C. to about 150° C. In addition, Li(I), Cu(I), or Mn(II)salts may be added to improve reactivity or specificity. Reactionsbetween compounds of formula 1 and compounds of formula A-B(OR_(y))₂,commonly known as Suzuki couplings utilize palladium catalysts such as,but not limited to, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),tris(dibenzylidineacetone)dipalladium or palladium diacetate. Apalladium ligand may be added such as 2-(dicyclohexylphosphino)biphenyl,tri-t-butylphosphine, or tris(2-furyl)phosphine and a base such as, butnot limited to, aqueous K₃PO₄, cesium carbonate, potassium carbonate orNa₂CO₃ in solvents such as toluene, dimethoxyethane, dioxane, water orDMF at a temperature from about 25° C. to about 150° C. The reaction mayalso be achieved with heating in a microwave reactor oven.

Although many organo stannanes are commercially available or describedin the literature, it is also possible to prepare additional stannanesfrom A-halides or A-triflates by treatment with a hexa-alkyldistannaneof formula ((R_(z))₃Sn)₂ in the presence of Pd(Ph₃P)₄. Similarly, in theabsence of commercially available organoboron reagents, A-B(OR_(y))₂ maybe prepared from the corresponding halides or triflates (A-halo orA-triflate) via metal exchange with an organolithium followed by theaddition of the alkyl borate.

Compounds of formula 2, wherein R₁ and R₂ are as defined in formula (I)and A is a heteroaryl ring linked to the parent moiety through anitrogen atom may be prepared as illustrated in Scheme 2. The treatmentof compounds of formula 1 with a reagent of formula A-H, wherein the Hisa hydrogen on a nitrogen atom contained within the heteroaryl ring A, inthe presence of a base such as, but not limited to, sodium t-butoxide orcesium carbonate and a metal catalyst such as, but not limited to,copper metal, CuI or palladium diacetate and optionally with a ligandsuch as, but not limited to, BINAP, or tri-tertbutylphosphine willprovide compounds of formula 2.

As previously mentioned in Scheme 1, compounds of formula (I) may besynthesized utilizing Stille couplings as described in Scheme 3.Compounds of formula 3, wherein R_(ii) is defined in formula (I), whentreated with compounds of formula 4, wherein R₁ is defined in formula(I) and P₁ is a nitrogen protecting group such as, but not limited to,tert-butyloxycarbonyl or acetyl, in the presence ofdichlorobis(triphenylphosphine)palladium(II) and(thiophene-2-carbonyloxy)copper in toluene under heated conditions willprovide compounds of formula 5. Compounds of formula 5 when treated withconditions known to remove the protecting group such as hydrochloricacid or trifluoroacetic acid in a solvent such as acetic acid or dioxanewhen the protecting group is tert-butyloxycarbonyl or sodium hydroxide,lithium hydroxide, or potassium hydroxide in an aqueous mixture of THF,isopropanol, or dioxane when the protecting group is acetyl will providecompounds of formula 6 which are representative of compounds of formula(I) wherein A is (ii).

Compounds of formula 3 utilized in Scheme 3 to generate compounds offormula (I) may be prepared as outlined in Scheme 4. Compounds offormula 7, which are obtained from commercial sources or may be preparedaccording to methods known to one skilled in the art, when treated witheither 1,1,1-tributyl-N,N-dimethylstannamine or methylethyl(tributylstannyl)carbamate will provide compounds of formula 8.Alkynes of formula 8 when heated in the presence of compounds of formula9, wherein R_(ii) is defined in formula (I) and N₃ is an azide, willprovide compounds of formula 3.

As outlined in Scheme 5, compounds of formula 12 which arerepresentative of compounds of formula (I), wherein A is (ii) may beprepared accordingly. Compounds of formula 10 wherein R₁ is defined informula (I) and X₁ is iodo, bromo, chloro, or triflate, when treatedwith TMS acetylene in the presence of copper iodide,dichlorobis(triphenylphosphine)palladium(II) and triethylamine followedby treatment with tetrabutylammonium fluoride or potassium hydroxidewill provide compounds of formula 11. The reaction may be done in asolvent such as, but not limited to, DMF at ambient temperature or underheated conditions. Compounds of formula 11 when treated with R_(ii)—Cl,sodium azide, copper sulfate, and optionally with metallic copper, orsodium carbonate, L-proline, and sodium ascorbate under heatedconditions in a solvent such as dioxane or water, will provide compoundsof formula 12 which are representative of compounds of formula (I)wherein A is (ii).

Alternatively, compounds of formula 13 when treated with TMS-acetylenein the presence of copper iodide,dichlorobis(triphenylphosphine)palladium(II) and triethylamine followedby treatment with tetrabutylammonium fluoride or potassium hydroxidewill provide compounds of formula 14. The reaction may be done in asolvent such as, but not limited to, DMF at ambient temperature or underheated conditions. Compounds of formula 14 when treated with compoundsof formula A wherein R_(ii) is defined in formula (I), or sodium azide,copper sulfate and metallic copper under heated conditions will providecompounds of formula 15. Compounds of formula 15 when heated in thepresence of hydrazine in ethanol, will provide compounds of formula 16.Compounds of formula 16 when treated with di-tert-butyldicarbonate and acatalytic amount of DMAP in a solvent such as THF or acetonitrile willprovide compounds of formula 17. Compounds of formula 17 when treatedwith compounds of formula 18 in the presence of a base such as, but notlimited to, pyridine in a solvent such as dichloromethane followed bytreatment with trifluoroacetic acid will provide compounds of formula19. Compounds of formula 16 when treated with a carboxylic acid usingcarboxylic acid-amine coupling conditions known to one skilled in theart will provide compounds of formula 19A. Standard carboxylic acidamine coupling conditions include adding a coupling reagent such as, butnot limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI), 1,3dicyclohexylcarbodiimide (DCC),Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) with or without an auxiliary reagent such as, but not limited to,1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate(HOBT) in a solvent such as, but not limited to, dichloromethane.

Compounds of formula 24 which are representative of compounds of formula(I) may be prepared accordingly. Compounds of formula 20 wherein X₁ ishalo or triflate, when treated with the compound of formula 21, aceticanhydride and a base such as, but not limited to, potassium acetateunder heated conditions will provide compounds of formula 22. Compoundsof formula 22 when treated with sodium azide, copper sulfate, a basesuch as sodium carbonate and compounds of formula 23, wherein R_(ii) isdefined in formula (I) and are either available from commercial sourcesor may be prepared by one skilled in the art, will provide compounds offormula 24.

As outlined in Scheme 8, compounds of formula 29 and 30, which arerepresentative of compounds of formula (I), may be prepared accordingly.Compounds of formula 25, wherein R₁ is defined in formula (I) and X₁ ishalo or triflate, when treated with compounds of formula 23 copperiodide, dichlorobis(triphenylphosphine)palladium(II) and triethylaminein DMF at ambient temperature or under heated conditions will providecompounds of formula 27. Compounds of formula 27 when treated withcompounds of formula 9, under heated conditions, and either neat or in asolvent such as, but not limited to, dioxane, will provide compounds offormula 29 and 30.

Compounds of formula 32 which are representative of compounds of formula(I), wherein A is (vii), and R₁ and R_(vii) are defined in formula (I),may be prepared accordingly. Aldehydes of formula 31, wherein R_(vii) isdefined in formula (I) which may be obtained from commercial sources,when treated with hydroxylamine hydrochloride and aqueous sodiumhydroxide will provide an oxime intermediate which when oxidized withChloramine T trihydrate, followed by treatment with copper sulfate andcopper wire and compounds of formula 11 will provide compounds offormula 32.

Compounds of formula 38 which are representative of compounds of formula(I) wherein A is (x), are prepared accordingly. Compounds of formula 33wherein R₁ is defined in formula (I) which may be obtained fromcommercial sources or prepared by one skilled in the art, when treatedwith N,O-dimethylhydroxylamine using acid coupling conditions known toone skilled in the art will provide compounds of formula 34. Standardcarboxylic acid-amine coupling conditions include adding a couplingreagent such as, but not limited to,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinicchloride (BOPCl),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) with or without an auxiliary reagent such as, but not limited to,1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate(HOBT) in a solvent such as, but not limited to, dichloromethane.Compounds of formula 34 when treated with a Grignard reagent such asbenzylmagnesium bromide in a solvent such as tetrahydrofuran belowambient temperature will provide compounds of formula 35. Compounds offormula 35 when treated with a protecting group reagent such as, but notlimited to, di-tert-butyldicarbonate and a catalytic amount of DMAP in asolvent such as THF or acetonitrile will provide compounds of formula36. Compounds of formula 36 when treated with pyridinium tribromide in asolvent such as, but not limited to, THF with or without the use of heatwill provide compounds of formula 36A. Compounds of formula 36A whentreated with compounds of formula 37 with or without the use of heatfollowed by treating the product with conditions that will remove thenitrogen protecting group will provide compounds of formula 38. Commonlyused nitrogen-protecting groups as well as methods to remove them aredisclosed in T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).

Compounds of formula 36, wherein R₁ is defined in formula (I) and P₁ isa nitrogen protecting group, when treated with compounds of formula 39under heated conditions followed by treating the product with conditionsknown to one skilled in the art that will remove a nitrogen protectinggroup or as outlined in the literature, will provide compounds offormula 40 which are representative of compounds of formula (I) whereinA is (xvii).

As outlined in Scheme 12, compounds of formula 47 which arerepresentative of compounds of formula (I), wherein A is (x) may beprepared accordingly. Compounds of formula 41, wherein R₁ is defined informula (I), when treated with di-tert-butyldicarbonate and a catalyticamount of DMAP in a solvent such as THF or acetonitrile will providecompounds of formula 42. Treatment of compounds of formula 42 withtributyl(1-ethoxyvinyl)stannane anddichlorobis(triphenylphosphine)palladium(II) will provide compounds offormula 44. Compounds of formula 44 when treated with pyridiniumtribromide in THF will provide compounds of formula 45. Compounds offormula 45 when treated with compounds of formula 46 in a solvent suchas, but not limited to, ethanol, wherein R_(x) is defined in formula(I), will provide compounds of formula 47.

As shown in Scheme 13, compounds of formula 51 which are representativeof compounds of formula (I), wherein A is (iv), may be preparedaccordingly. Compounds of formula 48, wherein R₁ is defined in formula(I), and which are either available through commercial sources or may beprepared according to literature procedures or as outlined herein, whenheated in the presence of both compounds of formula 49 and compounds offormula 50, both of which are either commercially available or may beprepared by one skilled in the art using procedures described in theliterature, will provide compounds of formula 51.

As outlined in Scheme 14, compounds of formula 55 which arerepresentative of compounds of formula (I) wherein A is (xiv), (xv),(xvi) or (xvii), may be prepared accordingly. Compounds of formula (52),wherein R₁ is defined in formula (I), when treated with butyllithiumfollowed by treatment with DMF followed by an acidic work up willprovide compounds of formula 48. Compounds of formula 48 when treatedwith compounds of formula 53, wherein X is —CH—, —N— or —S—, Y is —CH—,—N— or a bond, and scandium tri(triflate) followed by treatment withcompounds of formula 54, wherein Z_(a) is define in formula (I) willprovide compounds of formula 55.

As outlined in Scheme 15, compounds of formula 56 which arerepresentative of compounds of formula (I) wherein A is (vii) may beprepared accordingly. Compounds of formula (II), wherein R₁ is definedin formula (I), when treated with a reagent such as, but not limited to,ethyl 2-chloro-2-(hydroxyimino)acetate with a base such as, but notlimited to, triethylamine will provide compounds of formula 56. Thereaction may be performed in a solvent such as but limited to tolueneand may require the use of heat.

As outlined in Scheme 16, compounds of formula 29 which arerepresentative of compounds of formula (I) wherein A is (ii) may beprepared accordingly. Compounds of formula (27), wherein R₁ is definedin formula (I), when treated with a compound of formula 9, R_(ii)C(O)Clor ICl, CuI, and triethylamine in a solvent such as, but not limited to,tetrahydrofuran will provide compounds of formula 29. The reaction maybe performed at ambient temperature or with the use of heat.

As outlined in Scheme 17, compounds of formula 57 which arerepresentative of compound of formula (I), wherein A is (vi), may beprepared accordingly. Compounds of formula 45, wherein R₁ is defined informula (I), when treated with ammonium formate and formic acid willprovide compound of formula 57.

As outlined in Scheme 18, compounds of formula 58 which arerepresentative of compounds of formula (I), wherein A is (vii), may beprepared accordingly. Compounds of formula 48, wherein R₁ is defined informula (I), when treated with nitromethane will provide compounds offormula 58 (Organic Preparations and Procedures International, 2001, 33,381-386).

As outlined in Scheme 19, compounds of formula 60 which arerepresentative of compounds of formula (I), wherein A is (vi), may beprepared accordingly. Compounds of formula 48, wherein R₁ is defined informula (I), when treated with 1-(isocyanomethylsulfonyl)-4-methylbenzene, 59, and a suitable base such as, but notlimited to, potassium carbonate in a solvent such as methanol ortetrahydrofuran and subsequently treated with a suitable acid such ashydrochloric acid will provide compounds of formula 60.

As outlined in Scheme 20, compound of formula 63 which arerepresentative of compounds of formula (I), wherein A is (vi), may beprepared accordingly. Compounds of formula 33, wherein R₁ is defined informula (I), when treated with a suitable chlorinating agent such asthionyl chloride will provide compounds of formula 61. Compounds offormula 61, when treated with 2-(trimethylsilyl)-2H-1,2,3-triazole, 62,in a solvent such as sulfolane will provide compound of formula 63.

As outlined in Scheme 21, compounds of formula 66 which arerepresentative of compounds of formula (I), wherein A is (ix), may beprepared accordingly. Compounds of formula 61, wherein R₁ is defined informula (I), when treated with hydrazine in a suitable solvent such astetrahydrofuran will provide compounds of formula 64. Compounds offormula 64, when treated with trimethylorthoformate, 65, in the presenceof a catalytic amount of p-toluene sulfonic acid in a solvent such astetrahydrofuran will provide compounds of formula 66.

As outlined in Scheme 22, compounds of formula 69 which arerepresentative of compounds of formula (I), wherein A is as defined informula (I) can be made accordingly. Compounds of formula 67, whereinR_(y) is hydrogen, alkyl, aryl or the two R_(y) groups together with theboron atom to which they are attached form a 1,3-dioxoborolane, in thepresence of a palladium catalyst using the Suzuki reaction conditionsdescribed in Scheme 1 in the presence of a heteroaryl iodide (A-I)provide compounds of formula 68. Compounds of formula 68 are transformedto compounds of formula 69 upon treatment with hydrazine as described inScheme 6.

As outlined in Scheme 23, compounds of formula 74 which arerepresentative of compounds of formula (I), wherein R_(ii) and R₄ are asdefined for formula (I) are prepared starting with compounds of formula70, wherein X₁ is iodo, bromo, or chloro. Treatment of compounds offormula 70 first with hydrazine and then with di-tert-butyldicarbonateas described in Scheme 6 furnishes compounds of formula 71. Compounds offormula 71 upon reaction with acid chlorides of formula 18 in thepresence of a base such as potassium carbonate in tetrahydrofuran atambient temperature over 2 to 8 hours provide compounds of formula 72.Alternatively, compounds of formula 72 can be made from compounds offormula 71 using the conditions described in Scheme 6. Compounds offormula 72 are reacted with (trimethylsilyl)acetylene under theconditions described in Schemes 5 and 6 to give compounds of formula 73.Compounds of formula 74 are obtained from compounds of formula 73 upontreatment with R_(ii)—N₃ in aqueous t-butanol in the presence ofcopper(II) sulfate and sodium(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olateat 40-80° C. over 1 to 6 hours.

As outlined in Scheme 24, compounds of formula 76, which arerepresentative of compounds of formula (I), wherein A and R₄ are asdefined for formula (I) are obtained from compounds of formula 75.Compounds of formula 75 can be treated with A-B(OR_(y))₂ wherein A isdefined as for formula (I) and R_(y) is hydrogen, alkyl, aryl or the twoR_(y) groups together with the boron atom to which they are attachedform a 1,3-dioxoborolane, in the presence of a palladium catalyst usingthe Suzuki reaction conditions described in Scheme 1 to give compoundsof formula 76.

As outlined in Scheme 25, compounds of formula 80, which arerepresentative of compounds of formula (I), wherein R_(ii) and R₄ are asdefined for formula (I) are prepared accordingly. Compounds of formula77 and 78 reacted under Stille coupling conditions described in Scheme 3supply compounds of formula 79. Compounds of formula 79 when reacted asdescribed in Scheme 6 provide compounds of formula 80.

As outlined in Scheme 26, compounds of formulas 82, 83, 84, and 85,which are representative of compounds of formula (I), wherein A, R₄, R₅,R_(a) and R_(j) are as defined for formula (I), are prepared fromcompounds of formula 81. Compounds of formula 81 can be treated with anacid chloride, 18, in solvent such as tetrahydrofuran in the presence ofa base such as potassium carbonate or triethylamine to give compounds offormula 82. An alternative solvent is dichloromethane and an alternativebase is pyridine. The acid chlorides can be prepared from thecorresponding carboxylic acids by treatment with oxalyl chloride with acatalytic amount of N,N-dimethylformamide. To prepare compounds offormula 83, compounds of formula 81 can be treated with R_(j)NCO inheated pyridine. Compounds of formula 84 are prepared from compounds offormula 81 by treatment with R₅SO₂Cl in pyridine at or near roomtemperature. Compounds of formula 85 are also prepared from compounds offormula 81 in a reductive amination reaction with R_(a)CHO in thepresence of a reducing agent such as sodium triacetoxyborohydride orsodium cyanoborohydride and acetic acid in a solvent such as1,2-dichloroethane at or near room temperature and subsequent treatmentwith trifluoroacetic acid in dichloromethane to remove thet-butoxycarbonyl protecting group.

As outlined in Scheme 27, compounds of formula 87, wherein A, R_(j) andR_(k) are defined for formula (I), can be prepared from compounds offormula 86. Compounds of formula 86 are prepared as described forcompounds of formula 82 in Scheme 26. Compounds of formula 86 can thenbe heated in the presence of an amine, HNR_(j)R_(k), and a base such astriethylamine in a solvent such as acetonitrile to give compounds offormula 87. Alternatively, heterocycles such as pyrrolidine, piperidine,piperazine, and morpholine can be substituted for the amine.

As outlined in Scheme 28, compounds of formula 89, wherein A, R₁, R₂,R₃, m, Z_(c) and Z_(d) are as defined for formula (I), can be preparedform compound of formula 88. Compounds of formula 88 can be prepared asdescribed in Schemes 1-4, 7-9, 22, 24, and 26. During the preparation ofcompounds of formula 88, the carboxylic acid moiety pendant on A can beprotected as an ester and subsequently hydrolyzed to expose thecarboxylic acid by methods known to one skilled in the art of organicsynthesis. Compounds of formula 88 when treated with an amine(HNZ_(c)Z_(d)) using carboxylic acid-amine coupling conditions known toone skilled in the art will provide compounds of formula 89. Standardcarboxylic acid amine coupling conditions include adding a couplingreagent such as, but not limited to,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1,3dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinicchloride (BOPCl),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) optionally in the presence of a base such as triethylamine ordiisopropylethylamine with or without an auxiliary reagent such as, butnot limited to, 1-hydroxy-7-azabenzotriazole (HOAT) or1-hydroxybenzotriazole hydrate (HOBT) in a solvent such as, but notlimited to, dichloromethane or N,N-dimethylformamide.

As outlined in Scheme 29, compounds of formula 85, which arerepresentative of compounds of formula (I), wherein A and R_(a) are asdefined for formula (I), are prepared from compounds of formula 69.Compounds of formula 85 are also prepared from compounds of formula 69in a reductive amination reaction with R_(a)CHO in the presence of areducing agent such as sodium triacetoxyborohydride or sodiumcyanoborohydride and acetic acid in a solvent such as1,2-dichloroethane, dichloromethane, or N,N-dimethylformamide at or nearroom temperature.

EXAMPLES

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

Example 1 5-(1-benzyl-1H-1,2,3-triazol-5-yl)-1H-indazole Compound with5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole Example 1A tert-Butyl5-iodo-1H-indazole-1-carboxylate

To an ice bath cooled solution of 4-iodo-2-methylaniline (20 g, 83.24mmol) in chloroform (250 mL) was added dropwise a solution of aceticanhydride (21.2 g, 208.11 mmol) in chloroform (50 mL). Upon completionof the addition, the mixture was stirred at room temperature for 1 hour.Potassium acetate (2.5 g, 24.97 mmol) and isoamylnitrite (22.3 mL,166.48 mmol) were added and the mixture was heated at 70° C. for 20hours. The mixture was cooled and quenched with saturated aqueous NaHCO₃to pH 7. The mixture was extracted with dichloromethane, and theorganics were dried over sodium sulfate and filtered. The solvent wasevaporated under reduced pressure. The crude solid was washed withmethanol, dissolved in tetrahydrofuran (200 mL) and treated with a warmsolution of KOH (60 g) in water (200 mL). The mixture was stirred for 15minutes and was treated with 6 N HCl to pH 1. The layers were separated,the organic layer was dried over sodium sulfate and filtered, and thesolvent was evaporated under reduced pressure. The crude solid wasdissolved in dichloromethane (500 mL) and triethylamine (23 mL, 166.48mmol), and di-tert-butyldicarbonate (23.6 g, 108.2 mmol) and a catalyticamount of dimethylaminopyridine (˜5 mg) were added. The mixture wasstirred at room temperature for 2 hours, diluted with water, extractedwith dichloromethane, and dried with sodium sulfate and filtered. Thesolvent was evaporated under reduced pressure to afford the titlecompound. MS (ESI+) m/z 344.9 (M+H)⁺.

Example 1B tert-Butyl5-((trimethylsilyl)ethynyl)-1H-indazole-1-carboxylate

Example 1A (10.81 g, 31.4 mmol),dichlorobis(triphenylphosphine)palladium(II) (1.1 g, 1.57 mmol), andcopper (I) iodide (365 mg, 1.92 mmol) were combined in triethylamine (70mL) under an inert atmosphere. Trimethylsilyl acetylene (5.0 mL, 36.0mmol) was added and the mixture was stirred at 60° C. overnight. Thesolvent was removed under reduced pressure and the resulting residue wasdissolved in methylene chloride and washed with 1 N hydrochloric acid.The mixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 5-40% ethyl acetate in hexanesto afford the title compound. MS (ESI+) m/z 215.0 (M−99)⁺.

Example 1C 5-Ethynyl-1H-indazole

Example 1B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). Asolution of 1 N potassium hydroxide (50 mL) was added, and the mixturewas stirred at ambient temperature for 1 hour. The solvent was removedunder reduced pressure, and the resulting slurry was dissolved in ethylacetate and washed with water and brine. The organic layer was driedover sodium sulfate and filtered, and the solvent was removed underreduced pressure to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 13.24 (s, 1H) 8.10 (s, 1H) 7.95 (s, 1H) 7.55 (d, J=8.82 Hz, 1H)7.39 (dd, J=8.48, 1.36 Hz, 1H) 4.03 (s, 1H).

Example 1D 5-(1-benzyl-1H-1,2,3-triazol-5-yl)-1H-indazole Compound with5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole

Into a microwave vial were added 100.0 mg (0.70 mmol) of Example 1C and94 mg (0.70 mmol) of benzyl azide. The mixture was heated at 160° C. for20 minutes using microwave irradiation (CEM-Discover, 100 Watts, 1minute ramp time). The mixture was dissolved in ethyl acetate andpurified by silica gel chromatography eluting with 75% ethyl acetate inhexane to afford the title compounds. ¹H NMR (300 MHz, DMSO-d₆) δ ppm13.28 (s, 1H) 13.12 (s, 1H) 8.61 (s, 1H) 8.23 (s, 1H) 8.13 (s, 1H) 8.11(s, 1H) 7.94 (s, 1H) 7.82-7.89 (m, 2H) 7.56-7.70 (m, 2H) 7.20-7.44 (m,9H) 6.97-7.02 (m, 2H) 5.69 (s, 2H) 5.65 (s, 2H). MS (CI) m/z 276 (M+H)⁺.

Example 2 5-(1H-1,2,3-triazol-5-yl)-1H-indazole

Into a microwave vial were added 100.0 mg (0.70 mmol) of Example 1C, 81mg (0.7 mmol) of trimethylsilyl azide, CuI (4 mg), anddimethylformamide/methanol (1 mL, 9:1). The mixture was heated at 160°C. for 20 minutes using microwave irradiation (CEM-Discover, 100 Watts,1 minute ramp time). The mixture was dissolved in ethyl acetate, and theorganic layer was washed with water. The organic layer was dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure, andpurified by silica gel chromatography eluting with 80% ethyl acetate inhexanes to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm13.16 (s, 1H) 8.31 (s, 1H) 8.25 (s, 1H) 8.13 (s, 1H) 7.87 (d, J=8.82 Hz,1H) 7.62 (d, J=8.82 Hz, 1H). MS (CI) m/z 186 (M+H)⁺.

Example 3 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole Example 3Atert-Butyl 5-iodo-1H-indazole-1-carboxylate

To an ice bath cooled solution of 4-iodo-2-methylaniline (20 g, 83.24mmol) in chloroform (250 mL) was added dropwise with an addition funnela solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50mL). Upon completion of the addition, the mixture was stirred at roomtemperature for 1 hour. Potassium acetate (2.5 g, 24.97 mmol) andisoamylnitrite (22.3 mL, 166.48 mmol) were added, and the mixture washeated at 70° C. for 20 hour. The mixture was then cooled and quenchedwith saturated aqueous NaHCO₃ to pH 7. The mixture was extracted withdichloromethane, dried over sodium sulfate, filtered, and the solventwas evaporated under reduced pressure. The crude solid was washed withmethanol, dissolved in tetrahydrofuran (200 mL) and treated with a warmsolution of KOH (60 g) in water (200 mL). The mixture was stirred for 15minutes and was treated with 6 N HCl to pH 1. The layers were separated,the organic layer was dried over sodium sulfate and filtered, and thesolvent was evaporated under reduced pressure. The crude material wasdissolved in dichloromethane (500 mL) and triethylamine (23 mL, 166.48mmol), and di-tert-butyldicarbonate (23.6 g, 108.2 mmol), and acatalytic amount of dimethylaminopyridine (˜5 mg) were added. Themixture was stirred at room temperature for 2 hours, quenched withwater, extracted with dichloromethane, and dried over sodium sulfate andfiltered. The solvent was evaporated under reduced pressure to affordthe title compound. MS (ESI+) m/z 344.9 (M+H)⁺.

Example 3B tert-Butyl5-((trimethylsilyl)ethynyl)-1H-indazole-1-carboxylate

Example 3A, (10.81 g, 31.4 mmol),dichlorobis(triphenylphosphine)palladium(II) (1.1 g, 1.57 mmol), andcopper (I) iodide (365 mg, 1.92 mmol) were combined in triethylamine (70mL) under an inert atmosphere. Trimethylsilyl acetylene (5.0 mL, 36.0mmol) was added and the mixture was stirred at 60° C. overnight. Thesolvent was removed under reduced pressure and the resulting residue wasdissolved in methylene chloride and washed with 1 N hydrochloric acid.The mixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 5-40% ethyl acetate in hexanesto afford the title compound. MS (ESI+) m/z 215.0 (M−99)⁺.

Example 3C 5-Ethynyl-1H-indazole

Example 3B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). Asolution of 1 N potassium hydroxide (50 mL) was added and the mixturewas stirred at ambient temperature for 1 hour. The solvent was removedunder reduced pressure, and the resulting slurry was dissolved in ethylacetate and washed with water and brine. The organic layer was driedover sodium sulfate, filtered, and the solvent was removed under reducedpressure to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm13.24 (s, 1H) 8.10 (s, 1H) 7.95 (s, 1H) 7.55 (d, J=8.82 Hz, 1H) 7.39(dd, J=8.48, 1.36 Hz, 1H) 4.03 (s, 1H).

Example 3D 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole

Example 3C (40 mg, 0.28 mmol), benzyl azide (37 mg, 0.28 mmol), CuSO₄(14 mg, 0.056 mmol) and Cu wire (14 mg) were combined in tert-butanol(0.5 mL) and water (0.5 mL) and heated in a CEM-Discover microwave for10 minutes at 125° C. and 100 Watts. To the mixture was added 1M HCl andwater, the product was extracted with dichloromethane, and purified bysilica gel chromatography (50% ethyl acetate in hexanes) to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (s, 1H) 8.60 (s,1H) 8.23 (s, 1H) 8.11 (s, 1H) 7.85 (d, J=8.59, 1.53 Hz, 1H) 7.59 (d,J=8.59 Hz, 1H) 7.26-7.49 (m, 5H) 5.65 (s, 2H). MS (ESI+) m/z 276.0(M+H)⁺.

Example 4 5-[1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

Into a 5 mL CEM Microwave reaction tube which contained a Teflon-coatedmicro-flea stirring bar were added 17.6 mg (0.124 mmol) of Example 3C,300 μL aqueous solution containing 7.80 mg (0.118 mmol) of sodium azide;followed by 15.79 μL (0.118 mmol; 21.80 mg 0.95 equivalents) of2-methyl-benzyl bromide (added neat). To the suspension were then added300 μL of tert-butanol; 25 mg of copper wire; and finally 50 μL of 1 Naqueous copper sulfate pentahydrate solution. The microwave reactionvessel was then capped and heated with stirring for 10 minutes at 125°C. at 100 Watts power on a CEM-Discover microwave. After cooling toambient temperature, the mixture was diluted with 0.25 N aqueous HCl;and the aqueous suspension was extracted with dichloromethane. Theorganic layer was washed with distilled water; saturated aqueous NaCl;and then dried over anhydrous sodium sulfate and filtered. The driedsolution was diluted with acetonitrile; and the soluble organic materialwas then filtered thru a glass wool plug which was overlaid withadditional anhydrous sodium sulfate. An aliquot of the filtrate was thenremoved for subsequent LC/MS analysis. Those solutions that containedthe desired triazole product were then evaporated in-vacuo and thenredissolved in 1.50 mL of 1:1 DMSO/methanol. The solution of the crudetriazole product was then purified by reverse-phase HPLC using anacetonitrile/water 0.1% TFA gradient elution method to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 2.37 (s, 3H) 5.66 (s, 2H)7.16-7.34 (m, 4H) 7.63 (d, J=8.54 Hz, 1H) 7.87 (d, J=8.70, 1.37 Hz, 1H)8.14 (s, 1H) 8.25 (s, 1H) 8.49 (s, 1H). MS (ESI+) m/z 289.9 (M+H)⁺.

Example 5 5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methylbenzylbromide with 3-methyl-benzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.58 (s, 1H) 8.25 (s, 1H)8.14 (s, 1H) 7.87 (d, J=8.85, 1.53 Hz, 1H) 7.64 (d, J=8.54 Hz, 1H) 7.30(t, J=7.63 Hz, 1H) 7.14-7.24 (m, 3H) 5.60 (s, 2H) 2.31 (s, 3H). MS(ESI+) m/z 289.8 (M+H)⁺.

Example 6 5-[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methylbenzylbromide with 4-methyl-benzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.55 (s, 1H) 8.24 (s, 1H)8.14 (s, 1H) 7.86 (d, J=8.54, 1.53 Hz, 1H) 7.63 (d, J=8.85 Hz, 1H)7.25-7.33 (m, 2H) 7.18-7.24 (m, 2H) 5.59 (s, 2H) 2.29 (s, 3H). MS (ESI+)m/z 290.1 (M+H)⁺.

Example 7 5-[1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3-methoxylbenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.59 (s,1H) 8.25 (s, 1H) 8.14 (s, 1H) 7.87 (d, J=8.54, 1.53 Hz, 1H) 7.64 (d,J=8.85 Hz, 1H) 7.33 (t, J=7.93 Hz, 1H) 6.89-7.00 (m, 3H) 5.62 (s, 2H)3.76 (s, 3H). MS (ESI+) m/z 306.1 (M+H)⁺.

Example 8 5-[1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2-fluorobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.57 (s, 1H)8.25 (s, 1H) 8.12-8.17 (m, 1H) 7.87 (d, J=8.54, 1.53 Hz, 1H) 7.64 (d,J=8.54 Hz, 1H) 7.41-7.49 (m, J=7.32, 7.32 Hz, 2H) 7.22-7.33 (m, J=7.02Hz, 2H) 5.71 (s, 2H). MS (ESI+) m/z 293.9 (M+H)⁺.

Example 9 5-[1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3-fluorobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.61 (s, 1H)8.25 (s, 1H) 8.15 (s, 1H) 7.87 (d, J=8.85, 1.53 Hz, 1H) 7.64 (d, J=8.54Hz, 1H) 7.41-7.51 (m, 1H) 7.15-7.28 (m, 3H) 5.68 (s, 2H). MS (ESI+) m/z293.8 (M+H)⁺.

Example 10 5-[1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with4-fluorobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.58 (s, 1H)8.24 (s, 1H) 8.14 (s, 1H) 7.86 (d, J=8.85, 1.53 Hz, 1H) 7.64 (d, J=8.85Hz, 1H) 7.46 (d, J=8.85, 5.49 Hz, 2H) 7.24 (t, J=9.00 Hz, 2H) 5.64 (s,2H). MS (ESI+) m/z 293.9 (M+H)⁺.

Example 11 5-[1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2-chlorobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.56 (s, 1H)8.26 (s, 1H) 8.14 (s, 1H) 7.88 (d, J=8.54, 1.53 Hz, 1H) 7.64 (d, J=8.54Hz, 1H) 7.55 (d, J=7.63, 1.53 Hz, 1H) 7.32-7.48 (m, 3H) 5.76 (s, 2H). MS(ESI+) m/z 309.8 (M+H)⁺.

Example 12 5-[1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3-chlorobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.62 (s, 1H)8.26 (s, 1H) 8.15 (s, 1H) 7.87 (d, J=8.54, 1.53 Hz, 1H) 7.64 (d, J=8.54Hz, 1H) 7.40-7.49 (m, J=7.63 Hz, 3H) 7.35 (d, J=6.41 Hz, 1H) 5.67 (s,2H). MS (ESI+) m/z 309.8 (M+H)⁺.

Example 13 5-[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with4-chlorobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.58 (s, 1H)8.24 (s, 1H) 8.15 (s, 1H) 7.86 (d, J=8.54, 1.53 Hz, 1H) 7.64 (d, J=8.85Hz, 1H) 7.45-7.52 (m, 2H) 7.38-7.44 (m, 2H) 5.65 (s, 2H). MS (ESI−) m/z307.7 (M−H)⁻.

Example 14 5-[1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2-bromobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.55 (s, 1H)8.26 (s, 1H) 8.14 (s, 1H) 7.88 (d, J=8.54, 1.53 Hz, 1H) 7.72 (d, J=7.93Hz, 1H) 7.64 (d, J=8.54 Hz, 1H) 7.41-7.50 (m, 1H) 7.27-7.40 (m, 2H) 5.74(s, 2H). MS (ESI+) m/z 353.5 (M+H)⁺.

Example 15 5-[1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2-nitrobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.57 (s, 1H)8.27 (s, 1H) 8.12-8.22 (m, 2H) 7.88 (d, J=8.54, 1.53 Hz, 1H) 7.75-7.83(m, 1H) 7.60-7.72 (m, 2H) 7.27 (d, J=7.63 Hz, 1H) 6.02 (s, 2H). MS(ESI+) m/z 320.8 (M+H)⁺.

Example 16 5-[1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3-nitrobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.65 (s, 1H)8.21-8.28 (m, 3H) 8.15 (s, 1H) 7.80-7.91 (m, 2H) 7.73 (t, J=7.78 Hz, 1H)7.65 (d, J=8.54 Hz, 1H) 5.83 (s, 2H). MS (ESI+) m/z 320.8 (M+H)⁺.

Example 17 5-[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with4-nitrobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.64 (s, 1H)8.22-8.31 (m, 3H) 8.15 (s, 1H) 7.88 (d, J=8.70, 1.37 Hz, 1H) 7.57-7.68(m, 3H) 5.83 (s, 2H). MS (ESI+) m/z 320.7 (M+H)⁺.

Example 182-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2-cyanobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.61 (s, 1H)8.26 (s, 1H) 8.15 (s, 1H) 7.93 (d, J=7.63 Hz, 1H) 7.88 (d, J=8.54, 1.53Hz, 1H) 7.72-7.80 (m, 1H) 7.57-7.68 (m, 2H) 7.53 (d, J=7.93 Hz, 1H) 5.86(s, 2H). MS (ESI+) m/z 300.9 (M+H)⁺.

Example 193-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3-cyanobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.63 (s, 1H)8.26 (s, 1H) 8.15 (s, 1H) 7.85-7.93 (m, 2H) 7.83 (d, J=7.63 Hz, 1H) 7.72(d, J=8.24 Hz, 1H) 7.56-7.68 (m, 2H) 5.74 (s, 2H). MS (ESI+) m/z 300.9(M+H)⁺.

Example 204-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with4-cyanobenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.62 (s, 1H)8.26 (s, 1H) 8.15 (s, 1H) 7.82-7.93 (m, J=8.24 Hz, 3H) 7.65 (d, J=8.54Hz, 1H) 7.54 (d, J=8.24 Hz, 2H) 5.78 (s, 2H). MS (ESI+) m/z 300.7(M+H)⁺.

Example 215-{1-[2-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2-trifluoromethylbenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.56(s, 1H) 8.27 (s, 1H) 8.15 (s, 1H) 7.89 (d, J=8.85, 1.53 Hz, 1H) 7.85 (d,J=7.93 Hz, 1H) 7.72 (t, J=7.63 Hz, 1H) 7.55-7.68 (m, 2H) 7.33 (d, J=7.93Hz, 1H) 5.85 (s, 2H). MS (ESI+) m/z 300.7 (M+H)⁺.

Example 225-{1-[3-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3-trifluoromethylbenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.65(s, 1H) 8.25 (s, 1H) 8.14 (s, 1H) 7.87 (d, J=8.70, 1.37 Hz, 1H) 7.77 (s,1H) 7.71-7.76 (m, 1H) 7.61-7.69 (m, 3H) 5.78 (s, 2H). MS (ESI+) m/z344.0 (M+H)⁺.

Example 235-{1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with4-trifluoromethylbenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.63(s, 1H) 8.25 (s, 1H) 8.14 (s, 1H) 7.87 (d, J=8.54 Hz, 1H) 7.78 (d,J=7.93 Hz, 2H) 7.63 (d, J=8.54 Hz, 1H) 7.58 (d, J=7.93 Hz, 2H) 5.78 (s,2H). MS (ESI+) m/z 344.2 (M+H)⁺.

Example 245-{1-[3-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3-trifluoromethoxybenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm8.64 (s, 1H) 8.25 (s, 1H) 8.14 (s, 1H) 7.87 (d, J=8.54 Hz, 1H) 7.64 (d,J=8.54 Hz, 1H) 7.56 (t, J=8.24 Hz, 1H) 7.31-7.45 (m, 3H) 5.73 (s, 2H).MS (ESI+) m/z 359.9 (M+H)⁺.

Example 255-{1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with4-trifluoromethoxybenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm8.61 (s, 1H) 8.25 (s, 1H) 8.14 (s, 1H) 7.87 (d, J=8.70, 1.37 Hz, 1H)7.63 (d, J=8.54 Hz, 1H) 7.52 (d, J=8.85 Hz, 2H) 7.40 (d, J=8.24 Hz, 2H)5.70 (s, 2H). MS (ESI+) m/z 359.9 (M+H)⁺.

Example 26 5-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with4-tert-butylbenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.58 (s,1H) 8.24 (s, 1H) 8.13 (s, 1H) 7.86 (d, J=8.85, 1.53 Hz, 1H) 7.63 (d,J=8.54 Hz, 1H) 7.42 (d, J=8.24 Hz, 2H) 7.32 (d, J=8.24 Hz, 2H) 5.60 (s,2H) 1.26 (s, 9H). MS (ESI+) m/z 332.1 (M+H)⁺.

Example 27 Methyl3-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzoate

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3-carbomethoxybenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.62(s, 1H) 8.25 (s, 1H) 8.14 (s, 1H) 7.92-7.99 (m, 2H) 7.87 (d, J=8.54,1.53 Hz, 1H) 7.68 (d, J=7.63 Hz, 1H) 7.63 (d, J=8.54 Hz, 1H) 7.58 (t,J=7.63 Hz, 1H) 5.75 (s, 2H) 3.86 (s, 3H). MS (ESI+) m/z 333.9 (M+H)⁺.

Example 28 Methyl4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzoate

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with4-carbomethoxybenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.62(s, 1H) 8.25 (s, 1H) 8.14 (s, 1H) 7.99 (d, J=8.24 Hz, 2H) 7.87 (d,J=8.85 Hz, 1H) 7.63 (d, J=8.54 Hz, 1H) 7.49 (d, J=8.24 Hz, 2H) 5.76 (s,2H) 3.85 (s, 3H). MS (ESI+) m/z 333.9 (M+H)⁺.

Example 29 5-[1-(2,4-dimethylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2,4-dimethylbenzylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.45 (s,1H) 8.24 (s, 1H) 8.13 (s, 1H) 7.86 (d, J=8.54 Hz, 1H) 7.62 (d, J=8.54Hz, 1H) 7.12 (d, J=7.93 Hz, 1H) 7.07 (s, 1H) 7.04 (d, J=7.63 Hz, 1H)5.60 (s, 2H) 2.32 (s, 3H) 2.26 (s, 3H). MS (ESI+) m/z 304.0 (M+H)⁺.

Example 30 5-[1-(3,5-dimethylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3,5-dimethylbenzylbromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.56 (s,1H) 8.24 (s, 1H) 8.13 (s, 1H) 7.87 (d, J=8.54 Hz, 1H) 7.63 (d, J=8.54Hz, 1H) 6.95-7.01 (m, 3H) 5.55 (s, 2H) 2.26 (s, 6H). MS (ESI+) m/z 304.2(M+H)⁺.

Example 31 5-[1-(2,3-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2,3-dichlorobenzylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.59 (s,1H) 8.26 (s, 1H) 8.14 (s, 1H) 7.88 (d, J=8.70, 1.37 Hz, 1H) 7.69 (d,J=8.09, 1.37 Hz, 1H) 7.63 (d, J=8.54 Hz, 1H) 7.44 (t, J=7.78 Hz, 1H)7.31 (d, J=7.78, 1.07 Hz, 1H) 5.81 (s, 2H). MS (ESI+) m/z 343.8 (M+H)⁺.

Example 32 5-[1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2,4-dichlorobenzylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.56 (s,1H) 8.25 (s, 1H) 8.13 (s, 1H) 7.87 (d, J=8.54 Hz, 1H) 7.72 (d, J=2.14Hz, 1H) 7.63 (d, J=8.54 Hz, 1H) 7.50 (d, J=8.39, 1.98 Hz, 1H) 7.40 (d,J=8.24 Hz, 1H) 5.74 (s, 2H). MS (ESI−) m/z 341.8 (M−H)⁻.

Example 33 5-[1-(2,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2,5-dichlorobenzylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.59 (s,1H) 8.26 (s, 1H) 8.14 (s, 1H) 7.88 (d, J=8.85 Hz, 1H) 7.63 (d, J=8.85Hz, 1H) 7.56-7.61 (m, 1H) 7.49-7.55 (m, 1H) 7.47 (d, J=2.44 Hz, 1H) 5.75(s, 2H). MS (ESI+) m/z 343.8 (M+H)⁺.

Example 34 5-[1-(3,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with3,5-dichlorobenzylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.64 (s,1H) 8.26 (s, 1H) 8.15 (s, 1H) 7.87 (d, J=8.85 Hz, 1H) 7.57-7.71 (m, 2H)7.44 (d, J=1.53 Hz, 2H) 5.69 (s, 2H). MS (ESI+) m/z 344.1 (M+H)⁺.

Example 355-{1-[2,4-bis(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 4, substituting 2-methyl-benzyl bromide with2,4-bis(trifluoromethyl)bromide. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm8.62 (s, 1H) 8.27 (s, 1H) 8.07-8.18 (m, 3H) 7.89 (d, J=8.70, 1.37 Hz,1H) 7.64 (d, J=8.54 Hz, 1H) 7.49 (d, J=7.93 Hz, 1H) 5.96 (s, 2H). MS(ESI+) m/z 411.7 (M+H)⁺.

Example 36N-cyclohexyl-6-(1H-indazol-5-yl)imidazo[2,1-b][1,3]thiazol-5-amineExample 36A 1H-indazole-5-carbaldehyde

To a solution of 5-bromoindazole (5 g, 25.38 mmol) in tetrahydrofuran(100 mL) cooled at −50° C. under argon was added dropwise a solution of1.6 M n-butyllithium in hexanes (40 mL, 63.44 mmol). Dimethylformamide(3.9 mL, 50.75 mmol) was added, and the mixture was allowed to warm toroom temperature and stirred for 15 minutes. The mixture was thenquenched with water, extracted with ethyl acetate, preabsorbed ontosilica gel and purified by silica gel chromatography eluting with agradient of 10-30% ethyl acetate in hexanes to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.03 (s, 1H) 8.45 (s, 1H)8.35 (s, 1H) 7.85 (dd, J=8.70, 1.37 Hz, 1H) 7.69 (d, J=8.54 Hz, 1H).

Example 36BN-cyclohexyl-6-(1H-indazol-5-yl)imidazo[2,1-b][1,3]thiazol-5-amine

Example 36A (50 mg, 0.34 mmol) and 2-aminothiazole (28 mg, 0.34 mmol)were combined with scandium triflate (8 mg, 0.017 mmol) in anhydrousmethanol (1 mL) in a 4 mL vial. The vial was sealed and shaken atambient temperature for 30 minutes. Cyclohexyl isocyanide (42 mL, 0.34mmol) was added, and the mixture was shaken for 2 days at roomtemperature. The mixture was purified by reverse-phase HPLC using anacetonitrile/water 0.1% TFA gradient elution method to afford the titlecompound as the TFA salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.12 (s, 1H)8.32 (s, 1H) 8.13 (s, 1H) 8.05 (d, J=8.85, 1.22 Hz, 1H) 7.92 (d, J=4.27Hz, 1H) 7.60 (d, J=8.54 Hz, 1H) 7.37 (d, J=3.66 Hz, 1H) 4.89 (s, 1H)2.78-2.94 (m, 1H) 1.73-1.83 (m, 2H) 1.58-1.68 (m, 2H) 1.45-1.53 (m, 1H)1.16-1.29 (m, 2H) 1.04-1.14 (m, 3H). MS (ESI+) m/z 338.1 (M+H)⁺.

Example 37 N-cyclohexyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-amine

The title compound was prepared according to the procedure outlined inExample 36B, substituting 2-aminothiazole with 2-aminopyridine. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 13.04 (s, 1H) 8.57 (s, 1H) 8.23-8.39 (m, 2H)8.11 (s, 1H) 7.57 (d, J=8.54 Hz, 1H) 7.46 (d, J=8.85 Hz, 1H) 7.12-7.21(m, 1H) 6.88 (t, J=6.71 Hz, 1H) 4.78 (d, J=5.80 Hz, 1H) 2.78-2.91 (m,1H) 1.69-1.77 (m, J=10.98 Hz, 2H) 1.57-1.67 (m, 2H) 1.45-1.53 (m, 1H)1.21-1.34 (m, 2H) 1.01-1.16 (m, 3H). MS (ESI+) m/z 332.1 (M+H)⁺.

Example 38 N-cyclohexyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrazin-3-amine

The title compound was prepared according to the procedure outlined inExample 36B, substituting 2-aminothiazole with 2-aminopyrazine. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 13.12 (s, 1H) 8.90 (d, J=1.22 Hz, 1H) 8.61 (s,1H) 8.37 (d, J=4.58, 1.53 Hz, 1H) 8.29 (d, J=8.70, 1.37 Hz, 1H) 8.15 (s,1H) 7.85 (d, J=4.58 Hz, 1H) 7.62 (d, J=8.85 Hz, 1H) 5.05 (d, J=6.71 Hz,1H) 2.81-2.99 (m, 1H) 1.70-1.77 (m, J=10.68 Hz, 2H) 1.58-1.67 (m, 2H)1.47 (s, 1H) 1.24-1.38 (m, 2H) 1.00-1.16 (m, 3H). MS (ESI+) m/z 333.1(M+H)⁺.

Example 39 5-[1-benzyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-1H-indazole

Into a 20 mL scintillation vial was added 50.0 mg (0.34 mmol) of Example36A. To the solid was added a 2.0 mL dimethylformamide solutioncontaining 0.46 mmol (49 mg) of benzylamine and 50 mg of powderedactivated 4

molecular sieves. The vial was then capped and heated at 60° C. for 4hours on an orbital shaker. The vial was allowed to cool to ambienttemperature; and was uncapped. To the suspension was added 32 mg (0.23mmol) of anhydrous potassium carbonate followed by 66 mg (0.23 mmol)α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile. The vial was then cappedand heated overnight at 60° C. on a shaker. The vial was removed fromthe shaker; allowed to cool to ambient temperature; and the resultingsuspension was filtered. The filtrate was evaporated under reducedpressure at medium heat on a Savant Speed Vac. The crude residues wereredissolved in 1:1 DMSO/methanol and purified by reverse-phase HPLCusing an acetonitrile/water TFA gradient elution method to afford thetitle compound as the TFA salt. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.01 (s,1H) 8.12 (s, 1H) 7.76 (s, 1H) 7.60 (d, J=8.48 Hz, 2H) 7.32-7.45 (m, 2H)7.09-7.30 (m, 6H) 6.96 (d, J=6.61, 2.88 Hz, 2H) 5.23 (s, 2H). MS (DCI)m/z 369 (M+H)⁺.

Example 40N-{3-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]propyl}-N,N-dimethylamine

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 39 substituting benzylamine withN¹,N¹-dimethylpropane-1,3-diamine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.49(s, 1H) 8.88 (s, 1H) 8.19 (s, 1H) 7.94 (s, 1H) 7.73 (d, J=8.81 Hz, 1H)7.29-7.44 (m, 3H) 7.17 (t, J=8.98 Hz, 2H) 4.01 (t, J=7.12 Hz, 2H)2.89-3.04 (m, J=10.51 Hz, 2H) 2.68 (s, 3H) 2.67 (s, 3H) 1.87-2.02 (m,2H). MS (DCI) m/z 364 (M+H)⁺.

Example 41N-cyclohexyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-amine

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 36B substituting pyrimidin-2-amine forthiazol-2-amine. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.21-13.41 (m, 1H)9.07 (d, J=5.80 Hz, 1H) 8.85 (d, J=3.05 Hz, 1H) 8.51 (s, 1H) 8.24 (s,1H) 8.14 (d, J=8.70, 1.37 Hz, 1H) 7.73 (d, J=8.85 Hz, 1H) 7.47-7.56 (m,1H) 5.25-5.41 (m, J=2.75 Hz, 1H) 2.81-2.91 (m, J=10.53, 10.53 Hz, 1H)1.74-1.83 (m, 2H) 1.56-1.66 (m, 2H) 1.43-1.50 (m, 1H) 1.24 (q, J=11.09Hz, 2H) 1.00-1.14 (m, 3H). MS (ESI+) m/z 333.1 (M+H)⁺.

Example 425-[4-(4-fluorophenyl)-1-(1-phenylethyl)-1H-imidazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 1-phenylethanamine for benzylamine. ¹H NMR (300MHz, CDCl₃) δ ppm 8.04 (s, 1H) 7.75-7.84 (m, 1H) 7.35-7.55 (m, 4H)7.20-7.31 (m, 5H) 6.76-7.01 (m, 4H) 5.09 (q, J=7.12 Hz, 1H) 1.82 (d,3H). MS (DCI) m/z 383 (M+H)⁺.

Example 432-(1H-indazol-5-yl)-N-isopropylimidazo[1,2-a]pyrimidin-3-amine

Example 36A (42 mg, 0.287 mmol) and 2-aminopyrimidine (27 mg, 0.284mmol) were combined with scandium triflate (7 mg, 0.014 mmol) inanhydrous methanol (2 mL) in a 4 mL vial. The vial was sealed and shakenat ambient temperature for 30 minutes. Isopropyl isocyanide (27 mL,0.286 mmol) was added and the mixture was shaken at ambient temperatureovernight, followed by 40° C. for 2 hours. The mixture was absorbed onsilica gel and purified using silica gel chromatography eluting using agradient of 0-5% methanol in dichloromethane to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.08 (s, 1H) 8.75 (d, J=6.95,1.86 Hz, 1H) 8.60 (s, 1H) 8.31 (d, J=8.82, 1.36 Hz, 1H) 8.20 (d, J=4.75Hz, 1H) 8.14 (s, 1H) 7.60 (d, J=8.82 Hz, 1H) 7.03 (d, J=6.78, 4.07 Hz,1H) 6.54 (d, J=4.75 Hz, 1H) 4.86 (d, J=5.09 Hz, 1H) 1.05 (d, J=6.10 Hz,6H). MS (ESI+) m/z 293.0 (M+H)⁺.

Example 44 4-(1H-indazol-5-yl)-N-phenyl-1,3-thiazol-2-amine Example 44Atert-Butyl 5-bromo-1H-indazole-1-carboxylate

5-Bromoindazole (4.40 g, 22.3 mmol) and a catalytic amount ofdimethylaminopyridine (˜50 mg) were dissolved in dichloromethane (100mL). Di-tert-butyl dicarbonate (5.43 g, 24.9 mmol) was added, and themixture was stirred at ambient temperature overnight. The mixture wasabsorbed on silica gel and purified by silica gel chromatography elutingwith a gradient of 0-40% ethyl acetate in hexanes to afford the titlecompound. MS (ESI+) m/z 297.2 (M+H)⁺.

Example 44B tert-Butyl 5-acetyl-1H-indazole-1-carboxylate

Example 44A (5.12 g, 17.2 mmol), tributyl (1-ethoxyvinyl) tin (7.0 mL,20.7 mmol), and dichlorobis(triphenylphosphine)palladium(II) (672 mg,0.957 mmol) were combined in toluene (85 mL). Nitrogen was bubbled intothe mixture for 5 minutes, and the mixture was heated to 100° C. in asealed tube overnight. The mixture was absorbed on silica gel andpurified by silica gel chromatography eluting with a gradient of 0-40%ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z283.0 (M+Na)⁺.

Example 44C tert-Butyl 5-(2-bromoacetyl)-1H-indazole-1-carboxylate

Example 44B (1.60 g, 6.15 mmol) and pyridinium tribromide (1.98 g, 6.19mmol) were combined in tetrahydrofuran and heated to 40° C. for 2 hours.The mixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 0-40% ethyl acetate in hexanesto afford the title compound. MS (ESI+) m/z 360.9 (M+Na)⁺.

Example 44D 4-(1H-indazol-5-yl)-N-phenyl-1,3-thiazol-2-amine

Example 44C (71 mg, 0.208 mmol) and 1-phenyl-2-thiourea (33 mg, 0.217mmol) were combined in ethanol (300 mL) in a 4 mL vial. The vial wasshaken at 80° C. overnight. The mixture was absorbed on silica gel andpurified by silica gel chromatography eluting with a gradient ofmethanol in dichloromethane (0-5%) to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 13.08 (s, 1H) 10.23 (s, 1H) 8.32 (s, 1H) 8.14(s, 1H) 7.93 (d, J=8.59, 1.53 Hz, 1H) 7.75 (d, J=8.75, 1.07 Hz, 1H) 7.58(d, J=8.90 Hz, 1H) 7.36 (d, J=8.59, 7.36 Hz, 1H) 7.25 (s, 1H) 6.92-7.02(m, 1H). MS (ESI+) m/z 292.9 (M+H)⁺.

Example 45 5-(2-methyl-1,3-thiazol-4-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 44D substituting 1-phenyl-2-thiourea with thioacetamide. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.10 (s, 1H) 8.34 (s, 1H) 8.12 (s, 1H) 7.94(d, J=8.82, 1.70 Hz, 1H) 7.85 (s, 1H) 7.57 (d, J=8.82 Hz, 1H) 2.73 (s,3H). MS (ESI+) m/z 215.9 (M+H)⁺.

Example 46 N-ethyl-4-(1H-indazol-5-yl)-1,3-thiazol-2-amine

The title compound was prepared according to the procedure outlined inExample 44D substituting 1-phenyl-2-thiourea with ethylthiourea. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.04 (s, 1H) 8.21 (s, 1H) 8.09 (s, 1H) 7.83(d, J=8.65, 1.53 Hz, 1H) 7.58 (t, J=5.43 Hz, 1H) 7.51 (d, J=8.82 Hz, 1H)6.96 (s, 1H) 3.22-3.34 (m, 2H) 1.21 (t, J=7.29 Hz, 3H). MS (ESI+) m/z244.9 (M+H)⁺.

Example 47 N-benzyl-4-(1H-indazol-5-yl)-1,3-thiazol-2-amine

The title compound was prepared according to the procedure outlined inExample 44D substituting 1-phenyl-2-thiourea with 1-benzyl-2-thiourea.¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.02 (s, 1H) 8.21 (s, 1H) 8.12 (t,J=5.83 Hz, 1H) 8.08 (s, 1H) 7.83 (d, J=8.90, 1.53 Hz, 1H) 7.50 (d,J=8.90 Hz, 1H) 7.39-7.45 (m, 2H) 7.35 (t, J=7.52 Hz, 2H) 7.26 (t, J=7.21Hz, 1H) 6.97 (s, 1H) 4.54 (d, J=5.83 Hz, 1H). MS (ESI+) m/z 306.9(M+H)⁺.

Example 48 4-(1H-indazol-5-yl)-1,3-thiazol-2-amine

The title compound was prepared according to the procedure outlined inExample 44D substituting 1-phenyl-2-thiourea with thiourea. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.03 (s, 1H) 8.17 (s, 1H) 8.07 (s, 1H) 7.81 (d,J=8.82, 1.36 Hz, 1H) 7.50 (d, J=8.82 Hz, 1H) 7.01 (s, 2H) 6.92 (s, 1H).MS (ESI+) m/z 216.9 (M+H)⁺.

Example 49 4-(1H-indazol-5-yl)-N-(2-phenylethyl)-1,3-thiazol-2-amine

The title compound was prepared according to the procedure outlined inExample 44D substituting 1-phenyl-2-thiourea with 1-phenethylthiourea.¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.03 (s, 1H) 8.23 (s, 1H) 8.09 (s, 1H)7.85 (d, J=8.65, 1.53 Hz, 1H) 7.71 (t, J=5.43 Hz, 1H) 7.51 (d, J=8.82Hz, 1H) 7.26-7.36 (m, 4H) 7.18-7.26 (m, 1H) 6.97 (s, 1H) 3.47-3.59 (m,1H) 2.94 (t, J=7.44 Hz, 1H). MS (ESI+) m/z 321.0 (M+H)⁺.

Example 50 N-benzyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-amine

The title compound was prepared according to the procedure outlined inExample 43 substituting benzylisocyanide for isopropyl isocyanide. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.10 (s, 1H) 8.50-8.58 (m, 2H) 8.39 (d,J=4.07, 2.03 Hz, 1H) 8.25 (d, J=8.81, 1.36 Hz, 1H) 8.13 (s, 1H) 7.61 (d,J=8.81 Hz, 1H) 7.24 (s, 5H) 6.92 (d, J=6.78, 4.07 Hz, 1H) 5.44 (t,J=6.27 Hz, 1H) 4.13 (d, J=6.10 Hz, 2H). MS (ESI+) m/z 341.0 (M+H)⁺.

Example 51 N-butyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-amine

The title compound was prepared according to the procedure outlined inExample 43 substituting butylisocyanide for isopropyl isocyanide. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.09 (s, 1H) 8.70 (d, J=6.78, 2.03 Hz, 1H)8.55 (s, 1H) 8.44 (d, J=4.07, 2.03 Hz, 1H) 8.25 (d, J=8.82, 1.36 Hz, 1H)8.14 (s, 1H) 7.61 (d, J=8.82 Hz, 1H) 7.03 (d, J=6.78, 4.07 Hz, 1H) 4.90(t, J=5.93 Hz, 1H) 2.96 (s, 2H) 1.49 (s, 2H) 1.34 (s, 2H) 0.82 (t,J=7.29 Hz, 3H). MS (ESI+) m/z 307.0 (M+H)⁺.

Example 52N-(4-chlorophenyl)-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-amine

The title compound was prepared according to the procedure outlined inExample 43 substituting 4-chlorophenylisocyanide for isopropylisocyanide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.12 (s, 1H) 8.58 (dd,J=4.12, 1.98 Hz, 1H) 8.46 (d, J=15.87 Hz, 2H) 8.40 (dd, J=6.71, 1.83 Hz,1H) 8.06-8.16 (m, 2H) 7.58 (d, J=8.85 Hz, 1H) 7.18 (d, J=8.85 Hz, 2H)7.05 (dd, J=6.71, 3.97 Hz, 1H) 6.57 (d, J=8.85 Hz, 2H). MS (ESI+) m/z361.0 (M+H)⁺.

Example 532-(1H-indazol-5-yl)-N-(4-methoxyphenyl)imidazo[1,2-a]pyrimidin-3-amine

The title compound was prepared according to the procedure outlined inExample 43 substituting 4-methoxyphenylisocyanide for isopropylisocyanide. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.10 (s, 1H) 8.56 (dd,J=3.97, 2.14 Hz, 1H) 8.47 (s, 1H) 8.36 (dd, J=6.56, 1.98 Hz, 1H) 8.15(dd, J=8.70, 1.37 Hz, 1H) 8.10 (s, 1H) 7.99 (s, 1H) 7.57 (d, J=8.54 Hz,1H) 7.03 (dd, J=6.71, 4.27 Hz, 1H) 6.76 (d, J=8.85 Hz, 2H) 6.50 (d,J=8.85 Hz, 2H) 3.63 (s, 3H). MS (ESI+) m/z 357.4 (M+H)⁺.

Example 54 2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidine

The title compound was prepared according to the procedure outlined inExample 44D substituting 2-aminopyrimidine for 1-phenyl-2-thiourea. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.13 (s, 1H) 8.96 (dd, J=6.78, 2.03 Hz,1H) 8.51 (dd, J=4.41, 2.03 Hz, 1H) 8.42 (s, 1H) 8.36 (s, 1H) 8.15 (s,1H) 8.01 (dd, J=8.82, 1.70 Hz, 1H) 7.62 (d, J=8.48 Hz, 1H) 7.04 (dd,J=6.61, 4.24 Hz, 1H). MS (ESI+) m/z 236.1 (M+H)⁺.

Example 55 MethylN-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl]glycinate

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 36B substituting 2-aminopyridine for 2-aminothiazoleand methyl 2-isocyanoacetate for cyclohexyl isocyanide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 13.41 (s, 1H) 8.90 (d, J=6.75 Hz, 1H) 8.38 (s, 1H) 8.27(s, 1H) 7.84-7.98 (m, 3H) 7.77 (d, J=8.90 Hz, 1H) 7.55 (td, J=6.75, 1.23Hz, 1H) 5.95-6.06 (m, 1H) 3.87 (d, J=4.60 Hz, 2H) 3.51 (s, 3H). MS(ESI+) m/z 340.1 (M+H)⁺.

Example 56 N-benzyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-amine

The title compound was prepared according to the procedure outlined inExample 36B substituting 2-aminopyridine for 2-aminothiazole and benzylisocyanide for cyclohexyl isocyanide. The final product precipitated outof solution and was isolated after filtration. ¹H NMR (400 MHz, DMSO-d₆)d ppm 13.04 (s, 1H) 8.49 (s, 1H) 8.16-8.27 (m, 2H) 8.09 (s, 1H) 7.58 (d,J=8.90 Hz, 1H) 7.44 (d, J=8.90 Hz, 1H) 7.19-7.35 (m, 5H) 7.13 (ddd,J=8.98, 6.67, 0.92 Hz, 1H) 6.80 (td, J=6.75, 0.92 Hz, 1H) 5.32 (t,J=6.14 Hz, 1H) 4.12 (d, J=6.14 Hz, 2H). MS (ESI+) m/z 322.1 (M+H)⁺.

Example 57N-(4-chlorophenyl)-2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-amine

The title compound was prepared according to the procedure outlined inExample 36B substituting 2-aminopyridine for 2-aminothiazole and1-chloro-4-isocyanobenzene for cyclohexyl isocyanide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 13.06 (s, 1H) 8.39 (s, 2H) 8.05-8.14 (m, 2H) 7.94 (d,J=6.75 Hz, 1H) 7.62 (d, J=8.90 Hz, 1H) 7.55 (d, J=8.59 Hz, 1H) 7.28-7.34(m, 1H) 7.17 (d, J=8.90 Hz, 2H) 6.88-6.96 (m, J=6.75, 6.75 Hz, 1H) 6.53(d, J=8.59 Hz, 2H). MS (ESI+) m/z 360.0 (M+H)⁺.

Example 582-(1H-indazol-5-yl)-N-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-amine

The title compound was prepared according to the procedure outlined inExample 36B substituting 2-aminopyridine for 2-aminothiazole and1-isocyano-4-methoxybenzene for cyclohexyl isocyanide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 13.04 (s, 1H) 8.44 (s, 1H) 8.14 (d, J=8.90, 1.23 Hz, 1H)8.06 (s, 1H) 7.87-7.96 (m, 2H) 7.59 (d, J=8.90 Hz, 1H) 7.54 (d, J=8.59Hz, 1H) 7.24-7.33 (m, 1H) 6.86-6.93 (m, J=6.75, 6.75 Hz, 1H) 6.75 (d,J=9.21 Hz, 2H) 6.47 (d, J=9.21 Hz, 2H) 3.63 (s, 3H). MS (ESI+) m/z 356.1(M+H)⁺.

Example 59 tert-butyl4-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]piperidine-1-carboxylate

The title compound was prepared according to the procedure outlined inExample 39 substituting tert-butyl 4-aminopiperidine-1-carboxylate forbenzylamine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.32 (s, 1H) 8.14 (s, 1H)8.01 (s, 1H) 7.79 (s, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.24-7.39 (m, 2H) 6.97(t, J=8.90 Hz, 2H) 3.91-4.05 (m, 2H) 3.71-3.84 (m, 1H) 2.53-2.69 (m, 2H)1.76-1.94 (m, 4H) 1.35-1.40 (m, 9H). MS (DCI) m/z 462 (M+H)⁺.

Example 60 3,5-bis(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole Example60A tert-Butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate

To a solution of 5-bromoindazole (10 g, 50.75 mmol) in dimethylformamide(100 mL) was added KOH (10 g, 177.63 mmol). Over a period of 2 hours,iodine (20 g, 78.80 mmol) was added. The mixture was treated with asolution of Na₂S₂O₅ (20 g) in water (200 mL), extracted with ethylacetate, washed with brine, dried over sodium sulfate and filtered, andthe solvent was removed under reduced pressure. The solid was dissolvedin dichloromethane (350 mL) and treated with di-tert-butyl dicarbonate(14.4 g, 65.98 mmol) and dimethylaminopyridine (10 mg, 0.08 mmol). Themixture was stirred for 20 minutes at room temperature and passeddirectly through a bed of silica gel to afford the title compound. MS(DCI/NH₃) m/z 422.9 (M+H)⁺.

Example 60B tert-butyl 5-bromo-3-phenyl-1H-indazole-1-carboxylate andtert-butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate

To a solution of Example 60A (2.1 g, 5 mmol) in toluene (10 mL) wasadded Pd(PPh₃)₄ (173 mg, 0.15 mmol), a solution of Na₂CO₃ (1.1 g, 10mmol) in water (5 mL), and a solution of phenyl boronic acid (671 mg,5.5 mmol) in methanol (3 mL). The mixture was stirred at roomtemperature for 5 days, quenched with water, extracted with ethylacetate and purified by silica gel chromatography eluting with 5% ethylacetate/hexanes to afford the title compounds as a mixture. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.28 (d, J=1.53 Hz, 1H) 8.12 (d, J=8.85 Hz, 1H)7.97-8.04 (m, 3H) 7.80-7.86 (m, 2H) 7.75 (d, J=1.83 Hz, 1H) 7.54-7.63(m, 3H) 1.68 (s, 9H) 1.64 (s, 9H). MS (ESI+) m/z 373.9 (M+H)⁺.

Example 60C tert-Butyl3,5-bis((trimethylsilyl)ethynyl)-1H-indazole-1-carboxylate andtert-butyl 5-bromo-3-((trimethylsilyl)ethynyl)-1H-indazole-1-carboxylate

Example 60B (1 g, 2.55 mmol),dichlorobis(triphenylphosphine)palladium(II) (89 mg, 0.13 mmol),triethylamine (1.78 mL, 12.75 mmol), trimethylsilyl acetylene (0.432 mL,3.06 mmol), and CuI (24 mg, 0.13 mmol) were combined indimethylformamide (10 mL) and stirred at room temperature for 20 hours.The mixture was diluted with ethyl acetate, washed with water, andpurified by silica gel chromatography to afford the title compounds. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.10 (d, J=8.85 Hz, 1H) 8.07 (d, J=8.85 Hz,1H) 7.97 (d, J=1.83 Hz, 1H) 7.84 (s, 1H) 7.82 (dd, J=8.85, 1.83 Hz, 1H)7.71 (dd, J=8.54, 1.53 Hz, 1H) 1.65 (s, 18H) 0.33 (d, J=0.92 Hz, 18H).

Example 60D tert-butyl 3,5-diethynyl-1H-indazole-1-carboxylate andtert-butyl 5-bromo-3-ethynyl-1H-indazole-1-carboxylate

To a solution of Example 60C (350 mg, 0.85 mmol) in tetrahydrofuran (5mL) was added a 1M solution of TBAF in tetrahydrofuran (2 mL, 2 mmol).After 10 minutes, the solvent was evaporated under reduced pressure andthe crude mixture was purified by silica gel chromatography eluting with5% ethyl acetate in hexanes to afford the title compounds. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.12 (d, J=7.93 Hz, 1H) 8.07 (d, J=8.85 Hz, 1H) 8.01(d, J=1.53 Hz, 1H) 7.90 (s, 1H) 7.83 (dd, J=8.85, 1.83 Hz, 1H) 7.74 (dd,J=8.85, 1.53 Hz, 1H) 4.91 (s, 1H) 4.90 (s, 1H) 4.29 (s, 1H) 1.66 (s, 9H)1.65 (s, 9H).

Example 60E 3,5-bis(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 3D substituting Example 60D for Example 3C. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 13.35 (s, 1H) 8.76 (s, 1H) 8.71 (s, 1H) 8.70 (s, 1H) 7.92(d, J=8.61, 1.28 Hz, 1H) 7.64 (d, J=8.79 Hz, 1H) 7.38-7.43 (m, 8H)7.33-7.37 (m, 2H) 5.73 (s, 2H) 5.66 (s, 2H). MS (ESI+) m/z 433.2 (M+H)⁺.

Example 61 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-phenyl-1H-indazoleExample 61A tert-Butyl3-phenyl-5-((trimethylsilyl)ethynyl)-1H-indazole-1-carboxylate andtert-butyl 5-bromo-3-phenyl-1H-indazole-1-carboxylate

Example 60B (1 g, 2.55 mmol),dichlorobis(triphenylphosphine)palladium(II) (89 mg, 0.13 mmol),triethylamine (1.78 mL, 12.75 mmol), trimethylsilyl acetylene (0.432 mL,3.06 mmol), and CuI (24 mg, 0.13 mmol) were combined indimethylformamide (10 mL) and stirred at room temperature for 20 hours.The mixture was diluted with ethyl acetate and purified by silica gelchromatography to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δppm 8.29 (d, J=1.53 Hz, 1H) 8.09-8.19 (m, 3H) 7.96-8.03 (m, 4H) 7.83(dd, J=8.85, 1.83 Hz, 1H) 7.72 (dd, J=8.85, 1.53 Hz, 1H) 7.50-7.65 (m,6H) 1.68 (s, 18H) 0.26-0.27 (m, 9H).

Example 61B tert-Butyl 5-ethynyl-3-phenyl-1H-indazole-1-carboxylate andtert-butyl 5-bromo-3-phenyl-1H-indazole-1-carboxylate

The title compound was prepared according to the procedure outlined inExample 60D substituting Example 61A for Example 60C. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.28 (d, J=1.53 Hz, 1H) 8.21 (s, 1H) 8.16 (d, J=8.54 Hz,1H) 8.12 (d, J=8.85 Hz, 1H) 7.97-8.05 (m, 4H) 7.83 (dd, J=8.85, 1.83 Hz,1H) 7.75 (dd, J=8.85, 1.53 Hz, 1H) 7.53-7.64 (m, 6H) 4.27 (s, 1H) 1.68(s, 9H) 1.68 (s, 9H).

Example 61C 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-phenyl-1H-indazole

The title compound was prepared according to the procedure outlined inExample 3D substituting Example 61B for Example 3C. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 13.38 (s, 1H) 8.77 (s, 1H) 8.52 (s, 1H) 8.06 (d, J=7.33Hz, 2H) 7.98 (d, J=8.79 Hz, 1H) 7.69 (d, J=8.79 Hz, 1H) 7.53-7.61 (m,J=7.51, 7.51 Hz, 2H) 7.33-7.48 (m, 6H) 5.68 (s, 2H). MS (ESI+) m/z 352.0(M+H)⁺.

Example 62 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine Example62A 2-Fluoro-5-((trimethylsilyl)ethynyl)benzonitrile

5-Bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol),dichlorobis(triphenylphosphine)palladium(II) (652 mg, 0.929 mmol), andcopper (J) iodide (413 mg, 2.17 mmol) were combined in triethylamine (15mL) under an atmosphere of nitrogen. Trimethylsilyl acetylene (4.2 mL,29.7 mmol) was added and the mixture was heated to 100° C. The mixturesolidified and was monitored by LC/MS. After completion, the mixture wasdiluted with methylene chloride and washed with 1 N HCl. The organiclayer was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of ethyl acetate in hexanes(5-45%) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.09 (dd, J=6.10, 2.03 Hz, 1H) 7.77-7.97 (m, 1H) 7.54 (t, J=9.15 Hz, 1H)0.15-0.32 (m, 9H).

Example 62B 5-Ethynyl-2-fluorobenzonitrile

Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 70 mL)was added to a solution of Example 62A (5.05 g, 23.2 mmol) intetrahydrofuran (50 mL) and allowed to stir for 20 minutes. The mixturewas diluted with methylene chloride and washed with water. The organiclayer was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 5-40% ethyl acetate in hexanesto afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.13 (dd,J=6.27, 2.20 Hz, 1H) 7.82-7.95 (m, 1H) 7.56 (t, J=8.99 Hz, 1H) 4.40 (s,1H).

Example 62C 5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

Example 62B (1.68 g, 11.6 mmol) was dissolved in tert-butanol (14 mL).Benzyl azide (2.14 g, 15.8 mmol) was added and the mixture wastransferred to 14 microwave vials (1.0 mL each). Water (0.5 mL), a smallpiece of copper wire, and a 1 M solution of copper (II) sulfate (0.5 mL)were added to each microwave vial and the vials were heated in aCEM-Discover microwave at 125° C. using 100 Watts for 10 minutes each.The vials were recombined, diluted with ethyl acetate, and washed withwater and brine. The organic material was absorbed on silica gel andpurified by silica gel chromatography eluting with a gradient of 5-50%ethyl acetate in hexanes to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.73 (s, 1H) 8.33-8.44 (m, 1H) 8.19-8.32 (m, 1H)7.56-7.70 (m, 1H) 7.28-7.47 (m, 5H) 5.68 (s, 2H).

Example 62D 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

Hydrazine hydrate (18 mL) was added to Example 62C (1.93 g, 6.94 mmoL)in ethanol (10 mL). The mixture was heated to 95° C. overnight. Themixture was diluted with ethyl acetate and washed with water. Some ofthe product precipitated in the separatory funnel and was filtered toafford the title compound. The ethyl acetate layer was concentratedunder reduced pressure and the resulting solid was triturated withmethanol to afford additional title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 11.43 (s, 1H) 8.42 (s, 1H) 8.21 (s, 1H) 7.67 (d, J=8.82, 1.70 Hz,1H) 7.38 (s, 5H) 7.26 (d, J=8.48 Hz, 1H) 5.64 (s, 2H) 5.38 (s, 2H). MS(ESI+) m/z 291.0 (M+H)⁺.

Example 635-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-4-yl)carbonyl]-1H-indazol-3-amine

Example 62D (44 mg, 0.152 mmol), 1-methylpiperidine-4-carboxylic acidhydrochloride (27 mg, 0.150 mmol), and HATU (61 mg, 0.160 mmol) werecombined in tetrahydrofuran (2 mL). Diisopropylethylamine (110 mL, 0.631mmol) was added and the mixture was heated to 90° C. for 30 minutes. Themixture was diluted with methylene chloride and washed with 1 N sodiumhydroxide. The organic layer was absorbed on silica gel and purified bysilica gel chromatography eluting with a gradient of 5-15% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 8.58 (s, 1H) 8.47 (s, 1H) 8.26 (d, J=8.48 Hz, 1H) 7.97 (d, J=8.48,1.70 Hz, 1H) 7.38 (s, 5H) 6.58 (s, 2H) 5.67 (s, 2H) 3.35-3.47 (m, 1H)2.95 (d, J=11.19 Hz, 2H) 2.28 (s, 3H) 2.03-2.20 (m, 2H) 1.92 (s, 2H)1.77 (s, 2H). MS (ESI+) m/z 416.2 (M+H)⁺.

Example 64N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-methoxyacetamideExample 64A tert-Butyl3-amino-5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole-1-carboxylate

Example 62D (1.80 g, 6.20 mmol) was suspended in methylene chloride (100mL) with a catalytic amount of dimethylaminopyridine. A solution ofdi-tert-butyl dicarbonate (1.36 g, 6.23 mmol) in methylene chloride (50mL) was added dropwise over 1 hour. The mixture was absorbed on silicagel and purified by silica gel chromatography eluting with a gradient of0-5% methanol in dichloromethane to afford the title compound. MS (ESI+)m/z 391.1 (M+H)⁺.

Example 64BN-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-methoxyacetamide

Example 64A (45 mg, 0.115 mmol) was dissolved in methylene chloride (1.5mL) and pyridine (0.5 mL). Methoxy acetyl chloride (18 μL, 0.197 mmol)was added and the mixture was stirred at ambient temperature for 2hours. The solvents were removed using a warm stream of nitrogen, themixture was injected on a silica gel column, and the product waspurified by silica gel chromatography eluting with a gradient of 0-5%methanol in dichloromethane to afford tert-butyl5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-(2-methoxyacetamido)-1H-indazole-1-carboxylate(58 mg). The intermediate was dissolved in methylene chloride (2 mL) andtrifluoroacetic acid (1 mL) and stirred at ambient temperatureovernight. The solvents were removed under reduced pressure, and themixture was purified by preparative HPLC on a C8 column using a gradientof 10% to 100% acetonitrile/water containing 0.1% trifluoroacetic acidto afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.79 (s,1H) 10.16 (s, 1H) 8.59 (s, 1H) 8.20 (s, 1H) 7.83 (d, J=8.65, 1.53 Hz,1H) 7.51 (d, J=8.82 Hz, 1H) 7.37 (s, 5H) 5.64 (s, 2H) 4.12 (s, 2H) 3.42(s, 3H). MS (ESI+) m/z 363.0 (M+H)⁺.

Example 65N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide

Example 64A (81 mg, 0.207 mmol) was dissolved in methylene chloride (2mL) and pyridine (0.5 mL). Dimethylaminoacetylchloride hydrochloride,80% (120 mg, 0.607 mmol) was added in three portions over 2 hours andthe mixture was stirred at ambient temperature overnight.Trifluoroacetic acid (2 mL) was added and the mixture was stirred for 3hours. The mixture was diluted with methylene chloride and washed with 1N sodium hydroxide. The organic layer was absorbed on silica gel andpurified using silica gel chromatography eluting with a gradient of5-15% methanol in dichloromethane to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 12.77 (s, 1H) 10.05 (s, 1H) 8.58 (s, 1H) 8.24(s, 1H) 7.82 (d, J=8.65, 1.53 Hz, 1H) 7.50 (d, J=8.82 Hz, 1H) 7.30-7.44(m, 5H) 5.64 (s, 2H) 3.16-3.20 (m, 2H) 2.34 (s, 6H). MS (ESI+) m/z 376.1(M+H)⁺.

Example 66N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]butanamide

Example 64A (76 mg, 0.195 mmol) was dissolved in methylene chloride (2mL) and pyridine (0.2 mL). Butyryl chloride (26 μL, 0.250 mmol) wasadded and the mixture was stirred at ambient temperature for 2 hours.Trifluoroacetic acid (1 mL) was added and the mixture was stirred for 3hours. The mixture was diluted with methylene chloride and washed withwater. The organic layer was absorbed on silica gel and purified usingsilica gel chromatography eluting with a gradient of 1-8% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 12.70 (s, 1H) 10.30 (s, 1H) 8.57 (s, 1H) 8.23 (s, 1H) 7.81 (d,J=8.82 Hz, 1H) 7.49 (d, J=8.82 Hz, 1H) 7.37 (s, 5H) 5.64 (s, 2H) 2.39(t, J=7.29 Hz, 2H) 1.67 (s, 2H) 0.97 (t, J=7.46 Hz, 3H). MS (ESI+) m/z361.1 (M+H)⁺.

Example 675-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting piperidin-4-amine for benzylamine. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.28 (s, 1H) 8.14 (s, 1H) 7.94 (s, 1H) 7.78 (s, 1H)7.63-7.72 (m, 2H) 7.21-7.43 (m, 2H) 6.90-7.04 (m, 2H) 4.14 (d, J=5.59,1.86 Hz, 1H) 3.53-3.74 (m, J=5.76 Hz, 1H) 2.94 (d, J=12.21 Hz, 2H)2.21-2.35 (m, 2H) 1.74-1.88 (m, 3H). MS (DCI) m/z 362 (M+H)⁺.

Example 685-{4-(4-fluorophenyl)-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1H-imidazol-5-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 2-(1-methylpyrrolidin-2-yl)ethanamine forbenzylamine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.30 (s, 1H) 8.14 (s, 1H)7.86 (s, 1H) 7.82 (s, 1H) 7.68 (d, J=8.48 Hz, 1H) 7.24-7.47 (m, 3H)6.92-7.08 (m, 2H) 3.83 (t, J=7.80 Hz, 2H) 2.71-2.93 (m, 1H) 1.88-2.01(m, 3H) 1.74-1.88 (m, 1H) 1.00-1.83 (m, 7H). MS (DCI) m/z 390 (M+H)⁺.

Example 695-{4-(4-fluorophenyl)-1-[3-(4-methylpiperazin-1-yl)propyl]-1H-imidazol-5-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 3-(4-methylpiperazin-1-yl)propan-1-amine forbenzylamine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 8.13 (s, 1H)7.81 (s, 2H) 7.67 (d, J=8.48 Hz, 1H) 7.32-7.45 (m, 2H) 7.27 (d, J=8.48,1.36 Hz, 1H) 6.87-7.06 (m, 2H) 3.72-3.91 (m, 2H) 1.92-2.21 (m, 10H)1.91-2.20 (s, 3H) 1.51-1.66 (m, 2H). MS (ESI+) m/z 419 (M+H)⁺.

Example 70 Ethyl 5-(1H-indazol-5-yl)isoxazole-3-carboxylate

Example 3C (1.83 g, 12.9 mmol) was dissolved in toluene (60 mL) andtriethylamine (2.2 mL) and warmed to 90° C. Ethyl2-chloro-2-(hydroxyimino)acetate (1.89 g, 12.5 mmol) was dissolved intoluene (15 mL) and was added dropwise over 30 minutes. Following theaddition, the mixture was diluted with ethyl acetate and washed with 1 Nhydrochloric acid. The organic layer was concentrated under reducedpressure and the resulting residue was triturated with methanol toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.38 (s, 1H)8.43 (s, 1H) 8.23 (s, 1H) 7.92 (d, J=8.82, 1.36 Hz, 1H) 7.70 (d, J=8.82Hz, 1H) 7.44 (s, 1H) 4.41 (q, J=7.12 Hz, 2H) 1.35 (t, J=7.12 Hz, 3H). MS(ESI+) m/z 257.9 (M+H)⁺.

Example 71 5-(1H-indazol-5-yl)-N-methylisoxazole-3-carboxamide Example71A 5-(1H-indazol-5-yl)isoxazole-3-carboxylic Acid

Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100mL), methanol (10 mL), and water (10 mL). Potassium hydroxide (680 mg,12.1 mmol) was added, and the mixture was stirred at ambient temperaturefor 2 hours. The solvents were removed under reduced pressure, and theresulting residue was triturated with a mixture of 1 N hydrochloric acidand methanol to provide a solid that was filtered to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.37 (s, 1H) 8.39 (s, 1H)8.22 (s, 1H) 7.90 (dd, J=8.81, 1.36 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 7.30(s, 1H).

Example 71B 5-(1H-indazol-5-yl)-N-methylisoxazole-3-carboxamide

Example 71A (46 mg, 0.201 mmol), HATU (88 mg, 0.231 mmol), anddiisopropylethylamine (133 μL, 0.764 mmol) were combined intetrahydrofuran (2 mL). Monomethylamine (40% solution in water) (50 μL)was added, and the reaction was stirred at 50° C. for 2 hours. Themixture was diluted with methylene chloride and washed with 1 N sodiumhydroxide, 1 N hydrochloric acid, and brine. The organic layer wasabsorbed on silica gel and purified by silica gel chromatography elutingwith a gradient of 10-50% ethyl acetate in hexanes to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 8.72 (q, J=4.30Hz, 1H) 8.39 (s, 1H) 8.23 (s, 1H) 7.89 (d, J=8.65, 1.53 Hz, 1H) 7.69 (d,J=8.82 Hz, 1H) 7.28 (s, 1H) 2.80 (d, J=4.75 Hz, 3H). MS (ESI+) m/z 243.0(M+H)⁺.

Example 72 5-(3-benzylisoxazol-5-yl)-1H-indazole

Phenylacetaldehyde (90+%) (266 mg, 2.38 mmol) was dissolved intert-butanol (1 mL) and water (1 mL). Hydroxylamine hydrochloride (79mg, 1.14 mmol) was added followed by a 6 N solution of sodium hydroxide(19 μL, 31.7 mmol). The mixture was stirred for 30 minutes. Chloramine-Ttrihydrate (308 mg, 1.09 mmol) was added slowly over 5 minutes followedby the addition of copper (II) sulfate and a small piece of copper wire.Example 3C (154 mg, 1.08 mmol) was added and the mixture was stirred at50° C. for 2 hours then ambient temperature overnight. The mixture wasdiluted with methylene chloride and washed with water. The organic layerwas absorbed on silica gel and purified by silica gel chromatographyeluting with a gradient of 10-50% ethyl acetate in hexanes to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.31 (s, 1H) 8.28 (s,1H) 8.18 (s, 1H) 7.79 (dd, J=8.65, 1.53 Hz, 1H) 7.64 (d, J=8.81 Hz, 1H)7.13-7.46 (m, 5H) 6.83 (s, 1H) 4.04 (s, 2H). MS (ESI+) m/z 275.7 (M+H)⁺.

Example 73N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide

Example 64A (72 mg, 0.184 mmol) was dissolved in methylene chloride (2mL) and pyridine (0.2 mL). Benzoyl chloride (36 μL, 0.310 mmol) wasadded, and the mixture was stirred at ambient temperature for 2 hours.Trifluoroacetic acid (1 mL) was added and the mixture was stirred for 3hours. The mixture was diluted with methylene chloride and washed withwater. The organic layer was absorbed on silica gel and purified usingsilica gel chromatography eluting with a gradient of 1-8% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 12.88 (s, 1H) 10.81 (s, 1H) 8.63 (s, 1H) 8.16 (s, 1H) 8.06-8.13(m, 2H) 7.88 (d, J=8.82, 1.36 Hz, 1H) 7.59-7.64 (m, J=7.12 Hz, 1H)7.51-7.59 (m, 3H) 7.31-7.42 (m, 5H) 5.63 (s, 2H). MS (ESI+) m/z 395.1(M+H)⁺.

Example 74 5-(3-propylisoxazol-5-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 72 substituting butyraldehyde for phenylacetaldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.31 (s, 1H) 8.28 (s, 1H) 8.20 (s, 1H)7.76-7.85 (m, 1H) 7.63-7.70 (m, 1H) 6.88 (s, 1H) 2.63 (t, J=7.46 Hz, 2H)1.61-1.79 (m, 2H) 0.96 (t, J=7.29 Hz, 3H). MS (ESI+) m/z 228.0 (M+H)⁺.

Example 75 N-benzyl-4-(1H-indazol-5-yl)-5-phenyl-1,3-thiazol-2-amineExample 75A 1H-indazole-5-carboxylic Acid

The title compound was prepared according to the procedure outlined inExample 3A, substituting methyl 4-amino-3-methylbenzoate for4-iodo-2-methylaniline. During the final workup, addition of 6 N HCluntil pH 6 resulted in the formation of a solid, which was filtered,washed twice with water and dried in vacuo to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.32 (s, 1H) 12.83 (s, 1H) 8.46 (s, 1H)8.24 (s, 1H) 7.92 (dd, J=8.82, 1.70 Hz, 1H) 7.60 (d, J=8.82 Hz, 1H).

Example 75B N-Methoxy-N-methyl-1H-indazole-5-carboxamide

To a suspension of Example 75A (1.6 g, 10 mmol) andN,O-dimethylhydroxylamine (1.1 g, 11 mmol) in dichloromethane (40 mL)and dimethylformamide (10 mL) was added triethylamine (1.67 mL, 12 mmol)and EDC (2.1 g, 11 mmol), and the mixture was stirred at roomtemperature for 24 hours. The solvents were evaporated under reducedpressure, and the resulting residue was diluted with ethyl acetate andwashed with water. The organic layer was dried over sodium sulfate andpurified by silica gel column chromatography in ethyl acetate to affordthe title compound. MS (ESI+) m/z 206.0 (M+H)⁺.

Example 75C 1-(1H-indazol-5-yl)-2-phenylethanone

A solution of Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran (10 mL)was cooled under argon with an ice bath and treated with a 2M solutionof benzyl magnesium chloride in tetrahydrofuran (6.6 mL, 13.16 mmol).The reaction was stirred overnight at room temperature followed by theaddition of one more equivalent of benzyl magnesium chloride. Themixture was heated at 70° C. for 9 hours. One more equivalent ofbenzylmagnesium chloride was added, and the reaction was heated at 70°C. for another 90 minutes and was allowed to cool to room temperature.Aqueous saturated ammonium chloride was added, and the product wasextracted with ethyl acetate and purified by silica gel columnchromatography using 30% ethyl acetate in hexanes to afford the titlecompound. MS (ESI+) m/z 237.1 (M+H)⁺.

Example 75D tert-Butyl 5-(2-phenylacetyl)-1H-indazole-1-carboxylate

To a suspension of Example 75C (236 mg, 1 mmol) in dichloromethane (2mL) was added di-tert-butyl dicarbonate (327 mg, 1.5 mmol) and a pinchof dimethylaminopyridine (˜2 mg). The mixture was stirred for 15minutes, and passed through a bed of silica gel and eluted withdichloromethane. The solvent was evaporated under reduced pressure toafford the title compound. MS (ESI+) m/z 337.0 (M+H)⁺.

Example 75E 2-Bromo-1-(1H-indazol-5-yl)-2-phenylethanone

To a solution of Example 75D (336 mg, 1 mmol) in tetrahydrofuran (20 mL)heated at 40° C. with an oil bath was added dropwise with an additionfunnel a solution of pyridinium tribromide (352 mg, 1.1 mmol) intetrahydrofuran (20 mL) over 10 minutes. The reaction mixture was heatedfor an extra 2 hours, and was cooled, filtered, and the filtrate wasevaporated to afford the title compound. MS (ESI−) m/z 212.9 (M−H)⁻.

Example 75F N-benzyl-4-(1H-indazol-5-yl)-5-phenyl-1,3-thiazol-2-amine

A vial containing Example 75E (50 mg, 0.16 mmol) and 1-benzylthiourea(26 mg, 0.16 mmol) in ethanol (1 mL) was capped and heated in a heatershaker at 80° C. for 2 hours. The solution of the crude product waspurified by reverse-phase HPLC using an acetonitrile/water 0.1% TFAgradient elution method to afford the title compound as a TFA salt. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.99 (s, 1H) 8.33-8.37 (m, 1H) 8.01 (s,1H) 7.92-7.99 (m, 1H) 7.82 (s, 1H) 7.60-7.67 (m, J=7.83, 7.83 Hz, 1H)7.31-7.45 (m, 5H) 7.17-7.30 (m, 5H) 4.53 (d, J=4.60 Hz, 2H). MS (ESI+)m/z 383.0 (M+H)⁺.

Example 76 4-(1H-indazol-5-yl)-N,5-diphenyl-1,3-thiazol-2-amine

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 75F substituting 1-phenylthiourea for1-benzylthiourea. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.09 (s, 1H) 10.29(s, 1H) 8.05 (d, J=0.92 Hz, 1H) 7.89 (d, J=1.53, 0.92 Hz, 1H) 7.69 (d,J=8.59, 1.23 Hz, 2H) 7.47 (dt, J=8.59, 0.92 Hz, 1H) 7.40-7.44 (m, 1H)7.26-7.37 (m, 7H) 6.94-7.02 (m, J=7.36, 7.36 Hz, 1H). MS (ESI+) m/z369.0 (M+H)⁺.

Example 77 5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazoleExample 77A tert-butyl 5-(cyclopropylethynyl)-1H-indazole-1-carboxylate

Example 44A (2.31 g, 7.77 mmol), cyclopropyl acetylene (620 mg, 9.37mmol), dichlorobis(triphenylphosphine)palladium(II) (170 mg, 0.242mmol), and copper (J) iodide (92 mg, 0.483 mmol) were combined intriethylamine (10 mL) under an inert atmosphere of nitrogen. The mixturewas heated to 100° C. in a sealed tube for 4 hours. The mixture wasdiluted with methylene chloride and washed with 1 N hydrochloric acid.The organic layer was absorbed onto silica gel and purified by silicagel chromatography eluting with a gradient of 5-50% ethyl acetate inhexanes to afford the title compound. MS (ESI+) m/z 283.0 (M+H)⁺.

Example 77B 5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazole

Example 77A (145 mg, 0.51 mmol) and benzyl azide (82 mg, 0.62 mmol) wereheated neat in a CEM-Discover microwave at 150° C. and 150 Watts, for 10minutes. The crude mixture was dissolved in dichloromethane and purifiedby silica gel column chromatography using 50% ethyl acetate in hexanesas the eluent. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (s, 1H) 8.11 (d,J=5.52 Hz, 2H) 7.79 (d, J=8.59, 1.53 Hz, 1H) 7.60 (d, J=8.59 Hz, 1H)7.26-7.45 (m, 5H) 5.69 (s, 2H) 1.78-1.92 (m, 1H) 0.98-1.09 (m, 2H)0.31-0.45 (m, 2H). MS (ESI+) m/z 316.0 (M+H)⁺.

Example 78 5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl)-1H-indazole

The title compound was isolated as a by-product according to theprocedure outlined in Example 77B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.29(s, 1H) 8.14 (s, 1H) 7.80 (s, 1H) 7.65 (d, J=8.85 Hz, 1H) 7.29 (d,J=8.54, 1.53 Hz, 1H) 7.21-7.27 (m, 3H) 6.93 (d, J=7.48, 1.98 Hz, 2H)5.49 (s, 2H) 1.70-1.80 (m, 1H) 0.81-0.92 (m, 4H). MS (ESI+) m/z 316.0(M+H)⁺.

Example 79 2-(1H-indazol-5-yl)-3-phenylimidazo[1,2-a]pyrimidine

A vial containing Example 75E (80 mg, 0.25 mmol) and pyrimidin-2-amine(23 mg, 0.25 mmol) in ethanol (1 mL) was capped and heated in a heatershaker at 80° C. for 21 hours. The solution of the crude product waspurified by reverse-phase HPLC using an acetonitrile/water 0.1% TFAgradient elution method to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.69 (dd, J=4.30, 1.84 Hz, 1H) 8.59 (dd, J=6.75, 1.84 Hz,1H) 8.07 (s, 1H) 8.02 (s, 1H) 7.46-7.65 (m, 7H) 7.16 (dd, J=6.75, 3.99Hz, 1H). MS (ESI+) m/z 312.0 (M+H)⁺.

Example 805-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazoleExample 80A 4-(azidomethyl)tetrahydro-2H-pyran

4-(Iodomethyl)tetrahydro-2H-pyran (4.76 g, 21.1 mmol) was dissolved indimethyl sulfoxide (25 mL). Sodium azide (2.70 g, 41.5 mmol) was addedand the mixture was stirred at ambient temperature overnight. Theresulting slurry was diluted with diethyl ether and washed with water.The organic layer was concentrated under reduced pressure to afford thetitle compound. The product was used directly in subsequent reactionswithout characterization.

Example 80B5-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

Example 80A (122 mg, 0.864 mmol) and Example 3C (150 mg, 0.619 mmol)were combined in a microwave vial with tert-butanol (1 mL) and water (1mL). A small piece of copper wire followed by copper(II) sulfate (5 mg,0.02 mmol) was added, and the vial was stirred in a microwave(CEM-Discover) at 125° C. at 100 W for 10 minutes. The mixture wasdiluted with methylene chloride and washed with 1 N hydrochloric acid.The organic layer was absorbed onto silica gel and purified by silicagel chromatography eluting with a gradient of 0-5% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 13.11 (s, 1H) 8.53 (s, 1H) 8.22 (s, 1H) 8.12 (s, 1H) 7.85 (d,J=8.48, 1.36 Hz, 1H) 7.60 (d, J=8.82 Hz, 1H) 4.32 (d, J=7.12 Hz, 2H)3.85 (d, J=11.70, 2.54 Hz, 2H) 3.21-3.36 (m, 2H) 2.14 (s, 1H) 1.47 (s,2H) 1.30 (s, 2H). MS (ESI+) m/z 284.0 (M+H)⁺.

Example 81 5-[3-(piperidin-1-ylcarbonyl)isoxazol-5-yl]-1H-indazoleExample 81A 5-(1H-indazol-5-yl)isoxazole-3-carboxylic Acid

Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100mL), methanol (10 mL), and water (10 mL). Potassium hydroxide (680 mg,12.1 mmol) was added and the mixture was stirred at ambient temperaturefor 2 hours. The solvents were removed under reduced pressure, and theresulting residue was triturated with a mixture of 1 N hydrochloric acidand methanol to provide a solid that was filtered to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 8.41 (s, 1H)8.23 (s, 1H) 7.91 (dd, J=8.82, 1.70 Hz, 1H) 7.70 (d, J=8.82 Hz, 1H) 7.36(s, 1H).

Example 81B 5-[3-(piperidin-1-ylcarbonyl)isoxazol-5-yl]-1H-indazole

Example 81A (110 mg, 0.480 mmol), piperidine (55 μL, 0.556 mmol), andHATU (101 mg, 0.266 mmol) were combined in dimethylformamide (2 mL).Diisopropylethylamine (133 μL, 0.764 mmol) was added and the reactionwas stirred at 45° C. for 2 hours. The mixture was diluted with ethylacetate and washed with 1 N sodium hydroxide, 1 N hydrochloric acid,water (3 times), and brine. The organic layer was absorbed on silica geland purified by silica gel chromatography eluting with a gradient of0-5% methanol in dichloromethane to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.37 (s, 1H) 8.34-8.40 (m, 1H) 8.21-8.25 (m,1H) 7.84-7.91 (m, 1H) 7.66-7.72 (m, 1H) 7.20 (s, 1H) 3.59-3.69 (m, 2H)3.48-3.58 (m, 2H) 1.47-1.72 (m, 6H). MS (ESI+) m/z 297.0 (M+H)⁺.

Example 82 5-(1H-indazol-5-yl)-N-phenylisoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting aniline for piperidine. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 13.40 (s, 1H) 10.74 (s, 1H) 8.44 (s, 1H) 8.25 (s, 1H)7.93 (d, J=8.85, 1.53 Hz, 1H) 7.82 (d, J=7.63 Hz, 2H) 7.72 (d, J=8.85Hz, 1H) 7.44 (s, 1H) 7.35-7.42 (m, 2H) 7.16 (t, J=7.32 Hz, 1H). MS(ESI+) m/z 304.9 (M+H)⁺.

Example 83 N-cyclohexyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

Example 81A (53 mg, 0.231 mmol), cyclohexylamine (29 μL, 0.253 mmol),and HATU (101 mg, 0.266 mmol) were combined in dimethyl formamide (2mL). Diisopropylethylamine (133 μL, 0.764 mmol) was added, and thereaction was stirred at 45° C. for 2 hours. The mixture was diluted withethyl acetate and washed with 1 N sodium hydroxide, 1 N hydrochloricacid, water (3 times), and brine. The organic layer was absorbed onsilica gel and purified by silica gel chromatography eluting with agradient of 0-5% methanol in dichloromethane to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 8.58 (d, J=8.14Hz, 1H) 8.38 (s, 1H) 8.22 (s, 1H) 7.88 (d, J=8.81, 1.70 Hz, 1H) 7.69 (d,J=8.81 Hz, 1H) 7.28 (s, 1H) 3.69-3.86 (m, 1H) 1.77 (s, 4H) 1.60 (d,J=12.21 Hz, 1H) 1.20-1.46 (m, 4H) 1.06-1.20 (m, 1H). MS (ESI+) m/z 311.0(M+H)⁺.

Example 84 5-[3-(piperidin-1-ylmethyl)isoxazol-5-yl]-1H-indazole

Example 81B (22 mg, 0.0742 mmol) was dissolved in tetrahydrofuran (2.5mL) under an inert atmosphere of nitrogen. Lithium aluminum hydride (1.0M solution in tetrahydrofuran) (250 μL) was added and the mixture washeated to 70° C. for 20 minutes. Methanol was added, and the mixture wasabsorbed on silica gel and purified by silica gel chromatography elutingwith a gradient of methanol in dichloromethane (0-7%) to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.30 (s, 1H) 8.31 (s,1H) 8.20 (s, 1H) 7.84 (d, J=8.59, 1.53 Hz, 1H) 7.66 (d, J=8.59 Hz, 1H)6.92 (s, 1H) 3.54 (s, 2H) 2.32-2.46 (m, 2H) 1.47-1.59 (m, 4H) 1.33-1.46(m, 2H). MS (ESI+) m/z 283.0 (M+H)⁺.

Example 85 [5-(1H-indazol-5-yl)isoxazol-3-yl]methanol

Example 70 (84 mg, 0.366 mmol) was dissolved in tetrahydrofuran (8 mL).Lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (3.0 mL)was added in 1.0 mL portions over 2 hours. After the final addition, themixture was stirred for an additional 30 minutes. The mixture wasdiluted with methylene chloride and washed with water and the organiclayer was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 0-20% methanol indichloromethane to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 13.31 (s, 1H) 8.31 (s, 1H) 8.21 (s, 1H) 7.83 (d, J=8.59, 1.53 Hz,1H) 7.67 (d, J=8.90 Hz, 1H) 6.93 (s, 1H) 5.51 (s, 1H) 4.56 (d, J=2.45Hz, 1H). MS (ESI+) m/z 215.9 (M+H)⁺.

Example 86 5-(1H-indazol-5-yl)-N-(2-methoxyethyl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 2-methoxyethyl amine for piperidine. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 8.74 (t, J=4.92 Hz, 1H) 8.39 (s,1H) 8.23 (s, 1H) 7.89 (d, J=8.65, 1.53 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H)7.30 (s, 1H) 3.38-3.53 (m, 4H) 3.28 (s, 3H). MS (ESI+) m/z 287.0 (M+H)⁺.

Example 87 5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazoleExample 87A 1-(5-Iodo-1H-indazol-1-yl)ethanone

4-Iodo-2-methylaniline (30.2 g, 130 mmol) was dissolved in chloroform(300 mL) and cooled to 5° C. Acetic anhydride (35 mL, 343 mmol) wasadded dropwise, and the mixture was allowed to warm to ambienttemperature. Potassium acetate (4.21 g, 42.9 mmol) and isoamylnitrite(37 mL, 277 mmol) were added, and the mixture was heated to 70° C.overnight. The mixture was neutralized with saturated aqueous sodiumbicarbonate and extracted with methylene chloride. The solvents wereremoved under reduced pressure and the resulting residue was trituratedwith methanol to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δppm 8.41 (s, 1H) 8.33 (s, 1H) 8.05-8.21 (m, 1H) 7.90 (dd, J=8.48, 1.70Hz, 1H) 2.71 (s, 3H).

Example 87B 1-Benzyl-5-phenyl-4-(tributylstannyl)-1H-1,2,3-triazole

Phenylethynyltri-n-butyltin (8.25 g, 21.1 mmol) and benzyl azide (2.3mL, 18.4 mmol) were combined and heated to 150° C. overnight. Themixture was purified by silica gel chromatography eluting with agradient of 5-40% ethyl acetate in hexanes to afford the title compound.MS (ESI+) m/z 526.3 (M+H)⁺.

Example 87C1-(5-(1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-1-yl)ethanone

Example 87A (139 mg, 0.486 mmol), Example 87B (284 mg, 0.542 mmol),dichlorobis(triphenylphosphine)palladium(II) (40 mg, 0.057 mmol) andcopper thiophene-2-carboxylate (167 mg, 0.876 mmol) were combined intoluene (1.5 mL) in a microwave vial under an inert atmosphere ofnitrogen. The vial was heated in a microwave (CEM-Discover) to 150° C.at 125 Watts for 20 minutes. The mixture was absorbed on silica gel andpurified by silica gel chromatography eluting with a gradient of 5-40%ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z394.1 (M+H)⁺.

Example 87D 5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazole

Example 87C (95 mg, 0.242 mmol) was dissolved in tetrahydrofuran (2.0mL), methanol (1.0 mL) and water (1.0 mL), and potassium hydroxide (64mg, 1.14 mmol) was added. The mixture was stirred for 2 hours, anddiluted with ethyl acetate and washed with water. The organic layer wasabsorbed on silica gel and purified by silica gel chromatography elutingwith a gradient of 0-5% methanol in dichloromethane to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.08 (s, 1H) 8.00 (s, 1H)7.79 (s, 1H) 7.44-7.56 (m, 5H) 7.24-7.36 (m, 5H) 6.95-7.03 (m, 2H) 5.49(s, 2H). MS (ESI+) m/z 252.1 (M+H)⁺.

Example 88 5-(4-benzyl-1H-1,2,3-triazol-1-yl)-1H-indazole

Example 87A (969 mg, 3.39 mmol), 3-phenyl-1-propyne (392 mg, 3.37 mmol),sodium azide (278 mg, 4.28 mmol), sodium ascorbate (68 mg, 3.43 mmol),sodium carbonate (75 mg, 0.708 mmol), and L-proline (78 mg, 8.98 mmol)were combined in a 1:1 mixture of dimethyl sulfoxide and water (10 mL).Copper(II) sulfate pentahydrate (46 mg, 0.184 mmol) was added and themixture was stirred at 65° C. for 3 hours. 6 N Sodium hydroxide (1 mL)was added, and the mixture was stirred for 30 minutes to deprotect theindazole. The mixture was diluted with ethyl acetate and washed with 1 Nhydrochloric acid. The organic layer was concentrated under reducedpressure, and the resulting residue was triturated with methanol. Theremaining solids were absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 0-5% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 13.35 (s, 1H) 8.58 (s, 1H) 8.17-8.27 (m, 1H) 7.86 (d, J=8.82, 2.03Hz, 1H) 7.67-7.77 (m, 1H) 7.27-7.36 (m, 2H) 7.18-7.27 (m, 1H) 4.10 (s,1H). MS (ESI+) m/z 276.0 (M+H)⁺.

Example 895-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amineExample 89A 5-(Cyclopropylethynyl)-2-fluorobenzonitrile

5-Bromo-2-fluorobenzonitrile (3.06 g, 15.3 mmol),dichlorobis(triphenylphosphine)palladium(II) (478 mg, 0.681 mmol), andcopper(I) iodide (165 mg, 0.866 mmol) were combined in triethylamine (15mL) under an inert atmosphere of nitrogen. Cyclopropylacetylene (1.8 mL)was added, and the mixture was heated to 60° C. until it turned to ablack solid. The mixture was diluted with methylene chloride and washedwith 1 N hydrochloric acid. The organic layer was absorbed on silica geland purified by silica gel chromatography eluting with a gradient of5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+)m/z 319.0 (M+H)⁺.

Example 89B5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

Example 89A (211 mg, 1.14 mmol) and benzyl azide (143 μL, 1.14 mmol)were combined in a microwave (CEM-Discover) vial and heated to 160° C.using 100 Watts for 26 minutes. The mixture was absorbed on silica geland purified by silica gel chromatography eluting with a gradient of20-60% ethyl acetate in hexanes to afford a mixture of inseparabletriazole regiomers. The mixture of regiomers were treated with hydrazinehydrate (3.0 mL) and ethanol (3.0 mL) and heated to 90° C. for 1 hour.The mixture was diluted with methylene chloride and washed with water.The organic layer was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 1-6% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 11.43 (s, 1H) 8.07 (s, 1H) 7.63 (d, J=8.65, 1.53 Hz, 1H) 7.32-7.45(m, 3H) 7.24-7.32 (m, 3H) 5.68 (s, 2H) 5.40 (s, 2H) 1.69-1.83 (m, 1H)0.98-1.08 (m, 2H) 0.32-0.42 (m, 2H). MS (ESI+) m/z 331.1 (M+H)⁺.

Example 905-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl)-1H-indazol-3-amine

The title compound was isolated as a by-product according to theprocedure outlined in Example 89B. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.62(s, 1H) 7.79 (s, 1H) 7.32 (d, J=8.48 Hz, 1H) 7.20-7.27 (m, 3H) 7.15 (d,J=8.65, 1.53 Hz, 1H) 6.93 (d, J=7.12, 2.37 Hz, 2H) 5.49 (s, 2H) 5.45 (s,2H) 1.71-1.82 (m, 1H) 0.80-0.89 (m, 4H). MS (ESI+) m/z 331.1 (M+H)⁺.

Example 91 5-(3-isobutylisoxazol-5-yl)-1H-indazol-3-amine Example 91A2-fluoro-5-(3-isobutylisoxazol-5-yl)benzonitrile

The title compound was prepared according to the procedure outlined inExample 72 substituting isovaleraldehyde for phenylacetaldehyde andExample 62B for Example 3C. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.47 (dd,J=6.10, 2.03 Hz, 1H) 8.19-8.29 (m, 1H) 7.71 (t, J=8.99 Hz, 1H) 7.08 (s,1H) 2.56 (d, J=7.12 Hz, 2H) 1.86-2.10 (m, 1H) 0.94 (d, J=6.78 Hz, 6H).

Example 91B 5-(3-isobutylisoxazol-5-yl)-1H-indazol-3-amine

To Example 91A (75 mg, 0.307 mmol) was added hydrazine hydrate (1.5 mL)in ethanol (1.0 mL). The mixture was heated to 70° C. overnight in asealed vial. The mixture was diluted with methylene chloride and washedwith water. The organic layer was absorbed on silica gel and purified bysilica gel chromatography eluting with a gradient of 0-5% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 11.67 (s, 1H) 8.26 (s, 1H) 7.66 (dd, J=8.82, 1.70 Hz, 1H) 7.32 (d,J=8.48 Hz, 1H) 6.67 (s, 1H) 5.56 (s, 2H) 2.51-2.58 (m, 2H) 1.89-2.11 (m,1H) 0.95 (d, J=6.44 Hz, 6H). MS (ESI+) m/z 257.0 (M+H)⁺.

Example 92 5-(3-benzylisoxazol-5-yl)-1H-indazol-3-amine Example 92A5-(3-benzylisoxazol-5-yl)-2-fluorobenzonitrile

The title compound was prepared according to the procedure outlined inExample 72 substituting Example 62B for Example 3C. The crude productwas used in the next step without further purification orcharacterization.

Example 92B 5-(3-benzylisoxazol-5-yl)-1H-indazol-3-amine

To Example 92A (65 mg, 0.234 mmol) was added hydrazine hydrate (1.5 mL)in ethanol (1.0 mL). The mixture was heated to 70° C. overnight in asealed vial. The mixture was diluted with methylene chloride and washedwith water. The organic layer was absorbed on silica gel and purified bysilica gel chromatography eluting with a gradient of 0-20% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 11.67 (s, 1H) 8.26 (s, 1H) 7.66 (d, J=8.82, 1.70 Hz, 1H) 7.32 (d,J=8.48 Hz, 1H) 6.67 (s, 1H) 5.56 (s, 2H) 2.45-2.57 (m, 2H) 1.91-2.08 (m,1H) 0.95 (d, J=6.44 Hz, 6H). MS (ESI+) m/z 291.0 (M+H)⁺.

Example 93N-{2-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]ethyl}-N,N-dimethylamine

The title compound was prepared according to the procedure outlined inExample 39 substituting 2-dimethylaminoethylamine for benzylamine. ¹HNMR (500 MHz, c) δ ppm 13.28 (s, 1H) 8.14 (s, 1H) 7.78-7.87 (m, 2H) 7.68(d, J=8.54 Hz, 1H) 7.33-7.41 (m, 2H) 7.28 (d, J=8.54, 1.53 Hz, 1H)6.95-7.05 (m, 2H) 3.86 (t, J=6.56 Hz, 2H) 2.31 (t, J=6.71 Hz, 2H) 2.00(s, 6H).

Example 945-[4-(4-fluorophenyl)-1-(3-morpholin-4-ylpropyl)-1H-imidazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 3-morpholinopropylamine for benzylamine. ¹H NMR(500 MHz, DMSO-d₆/D₂O) δ ppm 13.28 (s, 1H) 8.14 (s, 1H) 7.79-7.87 (m,2H) 7.68 (d, J=8.24 Hz, 1H) 7.34-7.42 (m, 2H) 7.28 (d, J=8.54, 1.53 Hz,1H) 6.92-7.03 (m, 2H) 3.77-3.89 (m, 2H) 3.24-3.30 (m, 4H) 2.10 (t,J=6.56 Hz, 2H) 1.96-2.05 (m, 4H) 1.54-1.66 (m, 2H). MS (ESI+) m/z 406.1(M+H)⁺.

Example 955-[4-(4-fluorophenyl)-1-(3-pyrrolidin-1-ylpropyl)-1H-imidazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 3-pyrrolidinopropylamine for benzylamine. ¹H NMR(500 MHz, DMSO-d₆/D₂O) δ ppm 8.13 (d, J=0.92 Hz, 1H) 7.79-7.85 (m, 2H)7.68 (d, J=8.54 Hz, 1H) 7.38 (d, J=8.85, 5.49 Hz, 2H) 7.27 (d, J=8.54,1.53 Hz, 1H) 6.99 (t, J=9.00 Hz, 2H) 3.82-3.90 (m, 2H) 2.21 (t, J=6.71Hz, 2H) 2.08-2.18 (m, 4H) 1.56-1.65 (m, 2H) 1.44-1.53 (m, 4H). MS (ESI+)m/z 390.2 (M+H)⁺.

Example 965-{4-(4-fluorophenyl)-1-[2-(4-methylpiperidin-1-yl)ethyl]-1H-imidazol-5-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 2-(4-methylpiperidin-1-yl)ethanamine forbenzylamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 13.29 (s, 1H) 8.14 (s,1H) 7.83 (s, 1H) 7.81 (s, 1H) 7.67 (d, J=8.54 Hz, 1H) 7.32-7.40 (m, 2H)7.28 (dd, J=8.54, 1.53 Hz, 1H) 6.93-7.04 (m, 2H) 3.85 (t, J=6.56 Hz, 2H)2.60 (d, J=11.60 Hz, 2H) 2.37 (t, J=6.56 Hz, 2H) 1.71-1.85 (m, 2H) 1.45(d, J=11.29 Hz, 2H) 1.15-1.30 (m, 1H) 0.95-1.07 (m, 2H) 0.83 (d, J=6.71Hz, 3H) MS (ESI+) m/z 404.1 (M+H)⁺.

Example 975-[1-(1-benzylpiperidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 4-amino-N-benzylpiperidine for benzylamine. ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ ppm 13.32 (s, 1H) 8.14 (s, 1H) 8.02 (s, 1H)7.78 (s, 1H) 7.69 (d, J=8.54 Hz, 1H) 7.17-7.40 (m, 8H) 6.97 (t, J=8.85Hz, 2H) 3.50-3.63 (m, 1H) 3.40 (s, 2H) 2.82 (d, J=11.90 Hz, 2H)1.90-2.05 (m, 2H) 1.72-1.89 (m, 4H). MS (ESI+) m/z 452.2 (M+H)⁺.

Example 985-[4-(4-fluorophenyl)-1-(2-morpholin-4-ylethyl)-1H-imidazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 2-morpholinoethylamine for benzylamine. ¹H NMR(500 MHz, DMSO-d₆/D₂O) δ ppm 13.27 (s, 1H) 8.14 (s, 1H) 7.86 (s, 1H)7.81 (s, 1H) 7.67 (d, J=8.54 Hz, 1H) 7.33-7.42 (m, 2H) 7.29 (d, J=8.54Hz, 1H) 6.95-7.06 (m, 2H) 3.87 (t, J=6.41 Hz, 2H) 3.42-3.51 (m, 4H) 2.40(t, J=6.56 Hz, 2H) 2.21 (d, J=3.97 Hz, 4H). MS (ESI+) m/z 392.1 (M+H)⁺.

Example 995-[1-(1-benzylpyrrolidin-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 39 substituting 3-pyrrlidinobenzylamine for benzylamine. ¹H NMR(500 MHz, DMSO-d₆/D₂O) δ ppm 13.29 (s, 1H) 8.13 (s, 1H) 8.03 (s, 1H)7.76 (s, 1H) 7.67 (d, J=8.54 Hz, 1H) 7.29-7.38 (m, 6H) 7.20-7.28 (m, 2H)6.98 (t, J=9.00 Hz, 2H) 4.25-4.34 (m, 1H) 3.53-3.69 (m, 2H) 2.89-2.97(m, 1H) 2.84 (d, J=9.76, 3.05 Hz, 1H) 2.55 (d, J=10.07, 6.71 Hz, 1H)2.17-2.34 (m, 2H) 1.92-2.03 (m, 1H). MS (ESI+) m/z 438.1 (M+H)⁺.

Example 100

Example 100 has been removed and is not part of this document.

Example 1012-{4-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]piperidin-1-yl}-2-oxoethanol

The title compound was prepared according to the procedure outlined inExample 39 substituting 1-(4-aminopiperidin-1-yl)-2-hydroxyethanone forbenzylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 13.27 (s, 1H) 8.14 (s,1H) 7.99 (s, 1H) 7.81 (s, 1H) 7.69 (d, J=8.48 Hz, 1H) 7.25-7.39 (m, 4H)6.91-7.03 (m, 2H) 4.48 (t, J=5.43 Hz, 1H) 4.34-4.44 (m, 1H) 4.07 (t,J=5.59 Hz, 1H) 3.79-3.91 (m, 1H) 3.64-3.77 (m, 1H) 2.85 (m, 1H)2.77-2.90 (m, 5H). MS (DCI) m/z 420 (M+H)⁺.

Example 1025-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine Example102A 5-(1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

Example 87B (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg,0.790 mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg, 0.074mmol), and copper thiophene-2-carboxylate (226 mg, 1.19 mmol) werecombined in toluene (2 mL) in a microwave vial under an inert atmosphereof nitrogen. The vial was heated in a microwave (CEM-Discover) to 150°C. at 125 Watts for 20 minutes. The mixture was absorbed on silica geland purified by silica gel chromatography eluting with a gradient ofethyl acetate in hexanes (5-40%) to afford the title compound. MS (ESI+)m/z 355.1 (M+H)⁺.

Example 102B5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

Example 102A (120 mg, 0.339 mmol) was treated with hydrazine hydrate(1.0 mL) in ethanol (1.0 mL) and heated to 60° C. overnight. The mixturewas diluted with methylene chloride and washed with water. The organiclayer was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 0-5% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 11.40 (s, 1H) 8.06 (s, 1H) 7.42-7.55 (m, 3H) 7.23-7.33 (m, 5H)7.02-7.10 (m, 2H) 6.94-7.02 (m, 2H) 5.49 (s, 2H) 5.34 (s, 2H). MS (ESI+)m/z 367.1 (M+H)⁺.

Example 103 2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-2-ol

The title compound was prepared according to the procedure outlined inExample 88 substituting 2-methyl-3-butyn-2-ol for 3-phenyl-1-propyneexcept that the crude reaction mixture was quenched with 2 mL of 1 Naqueous NaOH; and stirred for 1.5 hours at ambient temperature. Thesuspension was then dried by heated forced nitrogen gas evaporationprior to extraction. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.51 (s, 1H)8.22-8.29 (m, 2H) 7.88 (d, J=9.00, 1.98 Hz, 1H) 7.77 (d, J=8.85 Hz, 1H)1.57 (s, 6H). MS (ESI+) m/z 244.0 (M+H)⁺.

Example 104 5-[4-(methoxymethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting methyl propargyl ether for 3-phenyl-1-propyne.¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.73 (s, 1H) 8.23-8.29 (m, J=1.83Hz, 2H) 7.88 (d, J=8.85, 2.14 Hz, 1H) 7.78 (d, J=9.15 Hz, 1H) 4.57 (s,2H) 3.35 (s, 3H). MS (ESI+) m/z 230.0 (M+H)⁺.

Example 1051-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]-1-phenylethanol

The title compound was prepared according to the procedure outlined inExample 88 substituting 2-phenyl-3-butyn-2-ol for 3-phenyl-1-propyne. ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.52 (s, 1H) 8.21-8.28 (m, 2H) 7.87 (d,J=8.85, 2.14 Hz, 1H) 7.76 (d, J=9.15 Hz, 1H) 7.51-7.57 (m, 2H) 7.34 (t,J=7.78 Hz, 2H) 7.24 (t, J=7.32 Hz, 1H) 1.92 (s, 3H). MS (ESI+) m/z 306.0(M+H)⁺.

Example 106 5-(4-propyl-1H-1,2,3-triazol-1-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting 1-pentyne for 3-phenyl-1-propyne. ¹H NMR (500MHz, DMSO-d₆/D₂O) δ ppm 8.50 (s, 1H) 8.20-8.30 (m, 2H) 7.87 (d, J=9.00,1.98 Hz, 1H) 7.77 (d, J=8.85 Hz, 1H) 2.71 (t, J=7.48 Hz, 2H) 1.64-1.78(m, 2H) 0.97 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 228.0 (M+H)⁺.

Example 107 1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-2-ol

The title compound was prepared according to the procedure outlined inExample 88 substituting pent-4-yn-2-ol for 3-phenyl-1-propyne. ¹H NMR(500 MHz, DMSO-d₆/D₂O) δ ppm 8.49 (s, 1H) 8.20-8.33 (m, 2H) 7.88 (dd,J=9.00, 1.98 Hz, 1H) 7.74-7.82 (m, 1H) 3.95-4.08 (m, 1H) 2.74-2.89 (m,2H) 1.16 (d, J=6.10 Hz, 3H). MS (ESI+) m/z 244.0 (M+H)⁺.

Example 108 3-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-1-ol

The title compound was prepared according to the procedure outlined inExample 88 substituting 4-pentyn-1-ol for 3-phenyl-1-propyne. ¹H NMR(500 MHz, DMSO-d₆/D₂O) δ ppm 8.50 (s, 1H) 8.28 (s, 1H) 8.23 (d, J=1.83Hz, 1H) 7.83-7.91 (m, 1H) 7.74-7.82 (m, 1H) 4.50 (t, J=6.41 Hz, 1H) 3.51(t, J=6.41 Hz, 2H) 2.77 (t, J=7.63 Hz, 2H) 1.80-1.90 (m, 2H)MS (ESI+)m/z 244.0 (M+H)⁺.

Example 1091-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-1,2,3-benzotriazole

The title compound was prepared according to the procedure outlined inExample 88 substituting 1-propargyl-1H-benzotriazole for3-phenyl-1-propyne. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.91 (s, 1H)8.21-8.29 (m, 2H) 8.07 (d, J=8.54 Hz, 1H) 7.99 (d, J=8.54 Hz, 1H) 7.84(d, J=9.00, 1.98 Hz, 1H) 7.72-7.81 (m, 1H) 7.57-7.65 (m, 1H) 7.41-7.52(m, 1H) 6.16 (s, 2H). MS (ESI−) m/z 315.0 (M−H)⁻.

Example 110 5-{4-[(phenylthio)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting phenyl propargyl sulfide for 3-phenyl-1-propyne.¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.59 (s, 1H) 8.26 (s, 1H) 8.21 (d,J=1.22 Hz, 1H) 7.80-7.86 (m, 1H) 7.72-7.79 (m, 1H) 7.43 (d, J=8.39, 1.37Hz, 2H) 7.35 (t, J=7.78 Hz, 2H) 7.22 (t, J=7.32 Hz, 1H) 4.38 (s, 2H). MS(ESI+) m/z 308.3 (M+H)⁺.

Example 111 5-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting cyclopropylacetylene for 3-phenyl-1-propyne. ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.46 (s, 1H) 8.25 (s, 1H) 8.20 (d,J=1.53 Hz, 1H) 7.84 (d, J=9.00, 1.98 Hz, 1H) 7.76 (d, J=8.85 Hz, 1H)1.97-2.14 (m, 1H) 0.93-1.06 (m, 2H) 0.77-0.91 (m, 2H). MS (ESI+) m/z226.0 (M+H)⁺.

Example 112 5-[4-(2-phenylethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting 1-phenyl-1-butyne for 3-phenyl-1-propyne. Theproduct was a 1:1 mixture of starting material and title compound. ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.48 (s, 1H) 8.25 (s, 1H) 8.21 (d,J=1.53 Hz, 1H) 8.06 (s, 1H) 7.81-7.89 (m, 1H) 7.73-7.80 (m, 1H) 7.61(dd, J=8.85, 1.53 Hz, 1H) 7.45 (d, J=8.54 Hz, 1H) 7.25-7.36 (m, 4H)7.17-7.25 (m, 1H) 3.04 (s, 4H). MS (ESI+) m/z 290.1 (M+H)⁺.

Example 113 5-[4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting 3-cyclohexyl-1-propyne for 3-phenyl-1-propyne.¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.49 (s, 1H) 8.21-8.29 (m, 2H) 7.88(d, J=9.00, 1.98 Hz, 1H) 7.77 (d, J=8.85 Hz, 1H) 2.61 (d, J=6.71 Hz, 2H)1.54-1.77 (m, 6H) 1.08-1.30 (m, 3H) 0.91-1.05 (m, 2H). MS (ESI+) m/z282.2 (M+H)⁺.

Example 114 5-(4-cyclopentyl-1H-1,2,3-triazol-1-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting cyclopentylacetylene for 3-phenyl-1-propyne. ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.52 (s, 1H) 8.19-8.30 (m, 2H) 7.88 (d,J=9.00, 1.98 Hz, 1H) 7.77 (d, J=8.85 Hz, 1H) 3.13-3.27 (m, 1H) 1.98-2.15(m, 2H) 1.57-1.84 (m, 6H). MS (ESI+) m/z 254.0 (M+H)⁺.

Example 115 1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]cyclohexanol

The title compound was prepared according to the procedure outlined inExample 88 substituting 1-ethynyl-1-cyclohexanol for 3-phenyl-1-propyne.¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.52 (s, 1H) 8.21-8.30 (m, J=1.53Hz, 2H) 7.89 (dd, J=9.00, 1.98 Hz, 1H) 7.77 (d, J=8.85 Hz, 1H) 2.16-2.46(m, 1H) 1.92-2.05 (m, 2H) 1.77-1.86 (m, 2H) 1.61-1.77 (m, 2H) 1.51-1.59(m, 1H) 1.42-1.51 (m, 2H) 1.28-1.40 (m, J=9.92, 2.90 Hz, 1H)MS (ESI+)m/z 284.0 (M+H)⁺.

Example 116 5-[4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting phenyl propargyl ether for 3-phenyl-1-propyne.¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.87 (s, 1H) 8.22-8.34 (m, 2H) 7.89(d, J=8.85, 1.83 Hz, 1H) 7.79 (d, J=9.15 Hz, 1H) 7.29-7.41 (m, 2H) 7.09(d, J=7.63 Hz, 2H) 6.99 (t, J=7.32 Hz, 1H) 5.25 (s, 2H). MS (ESI+) m/z292.0 (M+H)⁺.

Example 1175-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting N-propargyl thiomorpholine-sulfone for3-phenyl-1-propyne. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.81 (s, 1H)8.24-8.36 (m, 2H) 7.89 (d, J=9.00, 1.98 Hz, 1H) 7.80 (d, J=9.15 Hz, 1H)4.38 (s, 2H) 3.30-3.56 (m, J=39.36 Hz, 8H). MS (ESI+) m/z 332.9 (M+H)⁺.

Example 118 5-[4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting 1-phenyl-1-pentyne for 3-phenyl-1-propyne. ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ ppm 8.52 (s, 1H) 8.26 (s, 1H) 8.23 (d,J=1.53 Hz, 1H) 7.87 (d, J=9.00, 1.98 Hz, 1H) 7.76 (d, J=9.15 Hz, 1H)7.31 (t, J=7.32 Hz, 2H) 7.23-7.28 (m, 2H) 7.20 (t, J=7.32 Hz, 1H) 2.74(t, J=7.63 Hz, 2H) 2.65-2.72 (m, 2H) 1.95-2.05 (m, 2H). MS (ESI+) m/z304.2 (M+H)⁺.

Example 119[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](phenyl)methanoneExample 119A tert-Butyl 5-ethynyl-1H-indazole-1-carboxylate

To a solution of Example 3C (230 mg, 1.62 mmol) in dichloromethane (10mL) was added di-tert-butyl dicarbonate (459 mg, 2.1 mmol) and a pinchof dimethylaminopyridine (˜3 mg), and the mixture was stirred for 30minutes at room temperature. Water was added, and the product wasextracted with dichloromethane, dried over sodium sulfate, filtered, andthe solvent was evaporated under reduced pressure to afford the titlecompound. MS (ESI+) m/z 265.0 (M+Na)⁺.

Example 119B[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](phenyl)methanone

A vial under argon containing Example 119A (90 mg, 0.37 mmol), benzylazide (0.047 mL, 0.37 mmol), tetrahydrofuran (3 mL), triethylamine(0.062 mL, 0.44 mmol), CuI (71 mg, 0.37 mmol) and benzoyl chloride(0.059 mL, 0.51 mmol) was capped and shaken for 16 hours. The solventswere evaporated, and the product was purified by silica gel columnchromatography in 5-30% ethyl acetate in hexanes. The crude material wastreated with TFA (0.5 mL) in dichloromethane (1 mL) and purified byreverse-phase HPLC using an acetonitrile/water 0.1% TFA gradient elutionmethod to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm13.08 (s, 1H) 7.98 (s, 1H) 7.77 (s, 1H) 7.54 (d, J=8.24, 1.22 Hz, 2H)7.43-7.48 (m, 1H) 7.33-7.40 (m, 2H) 7.22-7.30 (m, 5H) 7.17-7.21 (m, 2H)5.74 (s, 2H). MS (ESI+) m/z 380.1 (M+H)⁺.

Example 120N,N-diethyl-N-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}amine

The title compound was prepared according to the procedure outlined inExample 88 substituting 1,1-diethylpropargylamine for3-phenyl-1-propyne. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.98 (s, 1H) 8.30(d, J=1.36 Hz, 1H) 8.27 (s, 1H) 7.85-7.93 (m, 1H) 7.75-7.83 (m, 1H) 4.53(d, J=4.07 Hz, 2H) 3.11-3.23 (m, 4H) 1.31 (t, J=7.12 Hz, 6H). MS (ESI+)m/z 271.0 (M+H)⁺.

Example 121 EthylN-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]-beta-alaninate

The title compound was prepared according to the procedure outlined inExample 43 substituting ethyl isocyanopropionate for isopropylisocyanide. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.09 (s, 1H) 8.71 (d,J=6.78, 2.03 Hz, 1H) 8.54 (s, 1H) 8.46 (d, J=4.24, 1.87 Hz, 1H) 8.23 (d,J=8.82, 1.36 Hz, 1H) 8.14 (s, 1H) 7.61 (d, J=8.82 Hz, 1H) 7.05 (d,J=6.78, 4.07 Hz, 1H) 5.03 (t, J=5.93 Hz, 1H) 3.96 (q, J=7.12 Hz, 2H)3.23 (q, J=6.22 Hz, 2H) 2.47-2.55 (m, 2H) 1.08 (t, J=7.12 Hz, 3H). MS(ESI+) m/z 351.1 (M+H)⁺.

Example 122 5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazoleExample 122A 1-Benzyl-5-methyl-4-(tributylstannyl)-1H-1,2,3-triazole

Tributyl(1-propynyl)tin (3.87 g, 11.8 mmol) and benzyl azide (2.2 mL,17.6 mmol) were combined and heated to 150° C. overnight. The mixturewas purified by silica gel chromatography eluting with a gradient of5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+)m/z 464.2 (M+H)⁺.

Example 122B1-(5-(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-1-yl)ethanone

Example 87A (235 mg, 0.821 mmol), Example 122A (380 mg, 0.822 mmol),dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.085 mmol), andcopper thiophene-2-carboxylate (325 mg, 1.23 mmol) were combined intoluene (2.0 mL) in a microwave vial under an inert atmosphere ofnitrogen. The vial was heated in a microwave (CEM-Discover) to 150° C.at 125 Watts for 20 minutes. The mixture was absorbed on silica gel andpurified by silica gel chromatography eluting with a gradient of 5-40%ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z332.2 (M+H)⁺.

Example 122C 5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazole

Example 122B (109 mg, 0.329 mmol) was dissolved in tetrahydrofuran (3.0mL) and water (0.5 mL), and potassium hydroxide (53 mg, 0.945 mmol) wasadded. The mixture was stirred for 2 hours, diluted with ethyl acetate,and washed with water. The organic layer was absorbed on silica gel andpurified by silica gel chromatography eluting with a gradient of 0-5%methanol in dichloromethane to afford the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.13 (s, 1H) 8.12 (s, 1H) 8.01 (s, 1H) 7.71-7.78(m, 1H) 7.59-7.66 (m, 1H) 7.31-7.45 (m, 3H) 7.23-7.29 (m, 2H) 5.65 (s,2H) 2.43 (s, 3H). MS (ESI+) m/z 290.1 (M+H)⁺.

Example 1235-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine Example123A 5-(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

Example 122A (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg,0.790 mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg, 0.074mmol), and copper thiophene-2-carboxylate (226 mg, 1.19 mmol) werecombined in toluene (2 mL) in a microwave vial under an inert atmosphereof nitrogen. The vial was heated in a microwave (CEM-Discover) at 150°C. at 125 Watts for 20 minutes. The mixture was absorbed on silica geland purified by silica gel chromatography eluting with a gradient of5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+)m/z 293.0 (M+H)⁺.

Example 123B5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

Example 123A (120 mg, 0.339 mmol) was treated with hydrazine hydrate(1.0 mL) in ethanol (1.0 mL) and heated to 60° C. overnight. The mixturewas diluted with methylene chloride and washed with water. The organiclayer was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of methanol in dichloromethane(0-5%) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.43 (s, 1H) 7.98 (s, 1H) 7.60 (d, J=8.65, 1.53 Hz, 1H) 7.27-7.44 (m,4H) 7.21-7.27 (m, 2H) 5.65 (s, 2H) 5.41 (s, 2H) 2.41 (s, 3H). MS (ESI+)m/z 305.1 (M+H)⁺.

Example 124N³-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]-β-alaninamide

Example 121 (42 mg, 0.120 mmol) and a solution of 7 N ammonia inmethanol (1.0 mL) were combined and heated to 60° C. overnight. Themixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of methanol in dichloromethane(1-7%) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm13.09 (s, 1H) 8.76 (d, J=6.78, 2.03 Hz, 1H) 8.56 (s, 1H) 8.45 (d,J=4.07, 2.03 Hz, 1H) 8.24 (d, J=8.82, 1.36 Hz, 1H) 8.15 (s, 1H) 7.61 (d,J=8.48 Hz, 1H) 7.32 (s, 1H) 7.03 (d, J=6.78, 4.07 Hz, 1H) 6.85 (s, 1H)4.93 (t, J=6.10 Hz, 1H) 3.11-3.23 (m, 2H) 2.32 (t, J=6.78 Hz, 2H). MS(ESI+) m/z 322.0 (M+H)⁺.

Example 125 5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amineExample 125A5-(1-Benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

A mixture of Example 62B (200 mg, 1.38 mmol), benzyl azide (0.176 mL,1.38 mmol), tetrahydrofuran (12 mL), triethylamine (0.230, 1.56 mmol),CuI (263 mg, 1.38 mmol) and ICl (0.069 mL, 1.38 mmol) under argon wasstirred at room temperature for 24 hours. The solvent was evaporated andthe crude mixture was dissolved in dichloromethane, loaded directly ontoa silica gel column and eluted with ethyl acetate/hexanes (10-20%) toafford the title compound. MS (ESI+) m/z 404.9 (M+H)⁺.

Example 125B5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

Example 125A (50 mg, 0.12 mmol) and hydrazine monohydrate (1 mL) inethanol (1 mL) were heated at 95° C. for 2 hours. Water was added, andthe solid was collected by filtration and further purified byreverse-phase HPLC using an acetonitrile/water 0.1% TFA gradient elutionmethod to afford the title compound as a TFA salt. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.07 (s, 1H) 8.30 (s, 1H) 7.83 (d, J=8.85, 1.53 Hz, 1H)7.44 (d, J=8.54 Hz, 1H) 7.38-7.43 (m, J=7.32, 7.32 Hz, 2H) 7.32-7.37 (m,1H) 7.23-7.27 (m, J=7.02 Hz, 2H) 5.74 (s, 2H) 4.00 (s, 2H). MS (ESI+)m/z 417.0 (M+H)⁺.

Example 126N-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}-N′-(3-methylphenyl)ureaExample 126A1-(3-(1-Benzyl-4-(3-cyano-4-fluorophenyl)-1H-1,2,3-triazol-5-yl)phenyl)-3-m-tolylurea

A vial under argon containing Example 125A (94 mg, 0.23 mmol),1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-m-tolylurea(prepared according to a procedure described in WO2004/113304) (990 mg,0.26 mmol), PdCl₂dppf.dichloromethane (19 mg, 0.02 mmol), potassiumcarbonate (64 mg, 0.46 mmol), DME (2 mL) and water (0.2 mL) was cappedand heated in a heater shaker at 80° C. for 90 minutes. The solventswere evaporated and the product was extracted withmethanol/dichloromethane. Silica gel column chromatography using 10%ethyl acetate in hexanes afforded the title compound. MS (ESI+) m/z503.2 (M+H)⁺.

Example 126BN-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}-N′-(3-methylphenyl)urea

Example 126A (25 mg, 0.05 mmol) and hydrazine monohydrate (0.5 mL) inethanol (2 mL) were heated at 80° C. for 1 hour. The crude mixture wasloaded onto a silica gel column and eluted with a gradient of 0-5%methanol in dichloromethane to afford the title compound. ¹H NMR (500MHz, DMSO-d₆) δ ppm 11.40 (s, 1H) 8.79 (s, 1H) 8.63 (s, 1H) 8.12 (s, 1H)7.57 (d, J=8.24, 1.22 Hz, 1H) 7.43 (t, J=1.83 Hz, 1H) 7.38 (t, J=7.93Hz, 1H) 7.23-7.34 (m, 4H) 7.08-7.22 (m, 4H) 7.03 (d, J=6.71 Hz, 2H) 6.88(d, J=7.63 Hz, 1H) 6.78 (d, J=7.32 Hz, 1H) 5.50 (s, 2H) 5.36 (s, 2H)2.26 (s, 3H). MS (ESI+) m/z 515.3 (M+H)⁺.

Example 1275-(1H-indazol-5-yl)-N-(2-isopropoxyethyl)isoxazole-3-carboxamide

In a 20 mL vial a solution of 81A (37 mg, 0.18 mmol) dissolved indimethylformamide (0.8 mL) was added, followed by the addition of HATU(61 mg, 0.18 mmol) dissolved in dimethylformamide (0.8 mL). Then asolution of 2-isopropoxyethanamine (20 mg, 0.20 mmol) dissolved indimethylformamide (0.9 mL) was added followed by diisopropylethylamine(42 mg, 0.36 mmol) dissolved in dimethylformamide (0.8 mL). The mixturewas then shaken at 40° C. for three hours. The crude reaction mixturewas filtered through a Si-carbonate cartridge (6 mL, 2 g) supplied bySilicycle Chemical Division with methanol, checked with LC/MS, andconcentrated to dryness. The residue was dissolved in 1:1 DMSO/methanoland purified by reverse phase HPLC (Agilent, 5%-100% TFA/water gradient,8 minute run). ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.38-8.43 (m, 1H)8.22-8.30 (m, 1H) 7.90 (d, 1H) 7.73 (d, 1H) 7.21-7.29 (m, 1H) 3.56-3.65(m, 1H) 3.52 (t, 2H) 3.43 (t, 2H) 1.10 (d, 6H). MS (ESI+) m/z 315(M+H)⁺.

Example 128 5-[3-(morpholin-4-ylcarbonyl)isoxazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 127 substituting morpholine for 2-isopropoxyethanamine. ¹H NMR(300 MHz, DMSO-d₆/D₂O) δ ppm 8.36-8.43 (m, 1H) 8.22-8.29 (m, 1H) 7.89(d, 1H) 7.72 (d, 1H) 7.11-7.22 (m, 1H) 3.68-3.72 (m, 4H) 3.61-3.68 (m,4H). MS (ESI+) m/z 299 (M+H)⁺.

Example 1295-(1H-indazol-5-yl)-N-(3-morpholin-4-ylpropyl)isoxazole-3-carboxamide

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 127 substituting 3-morpholinopropan-1-amine for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.37-8.46(m, 1H) 8.20-8.31 (m, 1H) 7.91 (d, 1H) 7.73 (d, 1H) 7.17-7.36 (m, 1H)3.98-4.08 (m, 2H) 3.57-3.73 (m, 2H) 3.42-3.51 (m, 2H) 3.35-3.41 (m, 2H)3.14-3.22 (m, 2H) 3.01-3.14 (m, 2H) 1.88-2.06 (m, 2H). MS (ESI+) m/z 356(M+H)⁺.

Example 130N-[2-(1H-imidazol-4-yl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 127 substituting 2-(1H-imidazol-4-yl)ethanamine for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.90-8.97(m, 1H) 8.34-8.46 (m, 1H) 8.20-8.32 (m, 1H) 7.90 (d, 1H) 7.72 (d, 1H)7.38-7.49 (m, 1H) 7.14-7.28 (m, 1H) 3.57 (t, 2H) 2.96 (t, 2H). MS (ESI+)m/z 323 (M+H)⁺.

Example 131(3R)-1-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperidin-3-ol

The title compound was prepared according to the procedure outlined inExample 127 substituting (R)-piperidin-3-ol hydrochloride for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.34-8.45(m, 1H) 8.19-8.30 (m, 1H) 7.89 (d, 1H) 7.72 (d, 1H) 7.13 (d, 1H)4.03-4.19 (m, 1H) 3.64-3.72 (m, 1H) 3.54-3.62 (m, 1H) 3.34-3.44 (m, 1H)3.20-3.32 (m, 1H) 2.99-3.10 (m, 1H) 1.67-2.03 (m, 2H) 1.36-1.61 (m, 2H).MS (ESI+) m/z 313 (M+H)⁺.

Example 1321-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperidine-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 127 substituting piperidine-3-carboxamide for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.36-8.45(m, 1H) 8.22-8.32 (m, 1H) 7.90 (d, 1H) 7.72 (d, 1H) 7.07-7.23 (m, 1H)4.27-4.56 (m, 1H) 3.91-4.05 (m, 1H) 3.09-3.37 (m, 1H) 2.85-3.04 (m, 1H)2.31-2.45 (m, 1H) 1.89-2.05 (m, 1H) 1.73-1.86 (m, 1H) 1.60-1.72 (m, 1H)1.36-1.55 (m, 1H). MS (ESI−) m/z 338 (M−H)⁻.

Example 1332-[2-(4-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperazin-1-yl)ethoxy]ethanol

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 127 substituting 2-(2-(piperazin-1-yl)ethoxy)ethanolfor 2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm8.39-8.48 (m, 1H) 8.19-8.32 (m, 1H) 7.92 (d, 1H) 7.74 (d, 1H) 7.17-7.27(m, 1H) 4.49-4.60 (m, 1H) 3.94-4.01 (m, 1H) 3.76-3.81 (m, 4H) 3.56-3.63(m, 2H) 3.51-3.56 (m, 2H) 3.33-3.43 (m, 3H) 3.13-3.23 (m, 1H) 2.65-2.75(m, 2H). MS (ESI+) m/z 386 (M+H)⁺.

Example 1345-{3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 127 substituting 1-methyl-1,4-diazepane for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.38-8.46(m, 1H) 8.22-8.32 (m, 1H) 7.85-7.98 (m, 1H) 7.75 (d, 1H) 7.22 (d, 1H)4.07-4.19 (m, 1H) 3.69-3.77 (m, 2H) 3.59-3.67 (m, 1H) 3.44-3.59 (m, 1H)3.35-3.44 (m, 1H) 3.24-3.35 (m, 2H) 2.84-2.95 (m, 3H) 2.66-2.74 (m, 1H)2.10-2.26 (m, 2H). MS (ESI+) m/z 326 (M+H)⁺.

Example 135N-(3-hydroxypropyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 127 substituting 3-aminopropan-1-ol for 2-isopropoxyethanamine.¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.36-8.45 (m, 1H) 8.20-8.30 (m, 1H)7.84-7.94 (m, 1H) 7.71 (d, 1H) 7.18-7.28 (m, 1H) 3.48 (t, 2H) 3.35 (t,2H) 1.64-1.78 (m, 2H). MS (ESI+) m/z 387 (M+H)⁺.

Example 136N-[(1R)-2-hydroxy-1-phenylethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 127 substituting (R)-2-amino-2-phenylethanol for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 9.11 (d, 1H)8.37-8.46 (m, 1H) 8.23-8.28 (m, 1H) 7.91 (d, 1H) 7.73 (d, 1H) 7.40-7.45(m, 2H) 7.32-7.39 (m, 2H) 7.23-7.32 (m, 2H) 5.05-5.13 (m, 1H) 3.66-3.72(m, 2H). MS (ESI+) m/z 349 (M+H)⁺.

Example 137N-[3-(1H-imidazol-1-yl)propyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 127 substituting 3-(1H-imidazol-1-yl)propan-1-amine for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 9.02-9.10(m, 1H) 8.40-8.44 (m, 1H) 8.25-8.29 (m, 1H) 7.87-7.95 (m, 1H) 7.71-7.82(m, 2H) 7.61-7.69 (m, 1H) 7.20-7.29 (m, 1H) 4.28 (t, 2H) 3.33 (t, 2H)2.06-2.19 (m, 2H). MS (ESI+) m/z 337 (M+H)⁺.

Example 1385-(1H-indazol-5-yl)-N-[3-(2-oxopyrrolidin-1-yl)propyl]isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 127 substituting 1-(3-aminopropyl)pyrrolidin-2-one for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.38-8.43(m, 1H) 8.24-8.30 (m, 1H) 7.87-7.93 (m, 1H) 7.73 (d, 1H) 7.22-7.26 (m,1H) 3.39 (t, 2H) 3.21-3.30 (m, 4H) 2.26 (t, 2H) 1.90-2.00 (m, 2H)1.70-1.79 (m, 2H). MS (ESI+) m/z 354 (M+H)⁺.

Example 139N-{2-[4-(aminosulfonyl)phenyl]ethyl}-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 127 substituting 4-(2-aminoethyl)benzenesulfonamide for2-isopropoxyethanamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 8.37-8.42(m, 1H) 8.24-8.29 (m, 1H) 7.86-7.93 (m, 1H) 7.70-7.80 (m, 3H) 7.47 (d,2H) 7.20-7.24 (m, 1H) 3.57 (t, 2H) 2.96 (t, 2H). MS (ESI+) m/z 412(M+H)⁺.

Example 140[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](3-chlorophenyl)methanone

The title compound was prepared according to the procedure outlined inExample 119B substituting 3-chlorobenzoyl chloride for benzoyl chloride.¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.09 (s, 1H) 7.99 (s, 1H) 7.77 (s, 1H)7.38-7.51 (m, 4H) 7.28-7.37 (m, 3H) 7.20-7.27 (m, 4H) 5.78 (s, 2H). MS(ESI+) m/z 414.1 (M+H)⁺.

Example 141[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](cyclopropyl)methanone

The title compound was prepared according to the procedure outlined inExample 119B substituting cyclopropanecarbonyl chloride for benzoylchloride. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.26 (s, 1H) 8.18 (s, 1H)8.08 (s, 1H) 7.61-7.70 (m, 2H) 7.29-7.40 (m, 3H) 7.24 (d, J=7.02 Hz, 2H)5.79 (s, 2H) 1.86-2.00 (m, 1H) 0.98-1.12 (m, 2H) 0.77-0.93 (m, 2H). MS(ESI+) m/z 344.1 (M+H)⁺.

Example 1425-[5-cyclopropyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazoleExample 142A5-Cyclopropyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-4-(tributylstannyl)-1H-1,2,3-triazole

Cyclopropyl acetylene (142 mg, 2.15 mmol) was added to1,1,1-tributyl-N,N-dimethylstannanamine (716 mg, 2.14 mmol) in hexane(3.0 mL) and stirred in a sealed vial at 70° C. for 2 hours. The mixturewas cooled to ambient temperature, and the vial was stirred unsealed for10 minutes. Example 80A (455 mg, 3.22 mmol) was added, and the vial wasresealed and heated to 130° C. overnight. The mixture was purified bysilica gel chromatography eluting with a gradient of ethyl acetate inhexanes (5-50%) to afford the title compound. MS (ESI+) m/z 498.3(M+H)⁺.

Example 142B1-(5-(5-Cyclopropyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazol-1-yl)ethanone

Example 142A (220 mg, 0.444 mmol), Example 87A (128 mg, 0.447 mmol),dichlorobis(triphenylphosphine)palladium(II) (33 mg, 0.047 mmol), andcopper thiophene-2-carboxylate (127 mg, 0.666 mmol) were combined intoluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen.The vial was sealed and heated 150° C. for 20 minutes. The mixture wasabsorbed on silica gel and purified by silica gel chromatography elutingwith a gradient of 5-70% ethyl acetate in hexanes to afford the titlecompound. MS (ESI+) m/z 366.0 (M+H)⁺.

Example 142C5-[5-cyclopropyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

Example 142B (46 mg, 0.126 mmol) was dissolved in tetrahydrofuran (2.0mL) and water (0.5 mL) and potassium hydroxide (80 mg, 1.43 mmol) wasadded. The mixture was stirred for 2 hours, and was diluted withmethylene chloride and washed with water. The organic layer was absorbedon silica gel and purified by silica gel chromatography eluting with agradient of 0-8% methanol in dichloromethane to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.19 (s, 1H) 7.96 (d, J=8.82 Hz,1H) 7.61 (d, J=7.80 Hz, 1H) 7.25-7.28 (m, 1H) 4.34 (d, J=6.44 Hz, 2H)4.02 (d, J=11.36, 3.56 Hz, 2H) 3.42 (t, J=11.53 Hz, 2H) 2.33-2.46 (m,1H) 1.81-1.95 (m, 1H) 1.59-1.70 (m, 2H) 1.43-1.58 (m, 2H) 1.23-1.28 (m,1H) 1.10-1.20 (m, 2H) 0.47-0.62 (m, 2H). MS (ESI+) m/z 324.1 (M+H)⁺.

Example 143N¹-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]methyl}glycinamideExample 143A2-((1-Benzyl-4-(tributylstannyl)-1H-1,2,3-triazol-5-yl)methyl)isoindoline-1,3-dione

N-Propargylphthalimide (2.35 g mg, 12.7 mmol) was added to1,1,1-tributyl-N,N-dimethylstannanamine (4.23 mg, 12.7 mmol) in hexane(3.0 mL) and stirred in a sealed vial at 70° C. for 2 hours. The mixturewas cooled to ambient temperature and the vial was stirred unsealed for10 minutes. Benzyl azide (2.0 mL, 16.0 mmol) was added and the vial wasresealed and heated to 130° C. overnight. The mixture was purified bysilica gel chromatography eluting with a gradient of 10-50% ethylacetate in hexanes to afford the title compound. MS (ESI+) m/z 609.3(M+H)⁺.

Example 143B2-((4-(1-Acetyl-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl)methyl)isoindoline-1,3-dione

Example 143A (567 mg, 0.934 mmol), Example 87A (268 mg, 0.934 mmol),dichlorobis(triphenylphosphine)palladium(II) (67 mg, 0.095 mmol), andcopper thiophene-2-carboxylate (268 mg, 1.41 mmol) were combined intoluene (2.5 mL) in a microwave vial under an inert atmosphere ofnitrogen. The vial was heated in a microwave (CEM-Discover) to 150° C.at 125 Watts for 20 minutes. The mixture was absorbed on silica gel andpurified by silica gel chromatography eluting with a gradient of 10-50%ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z477.2 (M+H)⁺.

Example 143C(1-Benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl)methanamine

Example 143B (140 mg, 0.294 mmol) was treated with hydrazine hydrate(0.7 mL) in ethanol (0.7 mL) and stirred at ambient temperatureovernight. The mixture was absorbed on silica gel and purified by silicagel chromatography eluting with a gradient of 1-6% methanol indichloromethane to afford the title compound. MS (ESI+) m/z 305.0(M+H)⁺.

Example 143DN¹-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]methyl}glycinamide

Example 143C (66 mg, 0.217 mmol), N-(tert-butoxycarbonyl)-glycine (39mg, 0.223 mmol), and HATU (85 mg, 0.224 mmol) were combined in methylenechloride (2.5 mL). Diisopropylethylamine (150 μL, 0.865 mmol) was addedand the mixture was stirred at ambient temperature overnight. Themixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 0-6% methanol indichloromethane to afford tert-butyl2-((1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl)methylamino)-2-oxoethylcarbamate.This carbamate was dissolved in tetrahydrofuran (2 mL) and 0.5 mL of asolution of 1 N hydrochloric acid in diethyl ether was added and themixture was stirred for 20 minutes at room temperature. The solventswere removed under reduced pressure, and diethyl ether was added to themixture and stirred at room temperature overnight. The solvent wasdecanted, and the resulting residue was dried under a stream of nitrogento afford the title compound as a hydrochloride salt. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 13.21 (s, 1H) 9.02 (t, J=5.09 Hz, 1H) 8.11-8.16 (m, 2H)8.06 (s, 2H) 7.75-7.82 (m, 1H) 7.64 (d, J=8.82 Hz, 1H) 7.30-7.45 (m, 3H)7.23-7.31 (m, 2H) 5.72 (s, 2H) 4.57 (d, J=5.09 Hz, 2H) 3.41 (q, J=5.76Hz, 2H). MS (ESI+) m/z 362.1 (M+H)⁺.

Example 144(4-fluorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone

The title compound was prepared according to the procedure outlined inExample 119B substituting 4-fluorobenzoyl chloride for benzoyl chlorideand Example 80A for benzyl azide. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.10(s, 1H) 8.00 (s, 1H) 7.72-7.80 (m, 3H) 7.38-7.44 (m, 1H) 7.30-7.36 (m,1H) 7.09-7.19 (m, 2H) 4.41 (d, J=7.12 Hz, 2H) 3.80 (d, J=11.36, 2.54 Hz,2H) 3.14-3.26 (m, 2H) 2.04-2.19 (m, 1H) 1.38-1.49 (m, 2H) 1.19-1.35 (m,2H). MS (ESI+) m/z 406.1 (M+H)⁺.

Example 145(4-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone

The title compound was prepared according to the procedure outlined inExample 119B substituting 4-chlorobenzoyl chloride for benzoyl chlorideand Example 80A for benzyl azide. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.10(s, 1H) 8.00 (s, 1H) 7.77 (s, 1H) 7.68 (d, J=8.48 Hz, 2H) 7.29-7.45 (m,4H) 4.42 (d, J=7.12 Hz, 2H) 3.81 (d, J=11.19, 2.71 Hz, 2H) 3.14-3.27 (m,2H) 2.03-2.19 (m, 1H) 1.38-1.51 (m, 2H) 1.22-1.36 (m, 2H). MS (ESI+) m/z422.1 (M+H)⁺.

Example 146(3-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone

The title compound was prepared according to the procedure outlined inExample 119B substituting 3-chlorobenzoyl chloride for benzoyl chlorideand Example 80A for benzyl azide. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.04(s, 1H) 7.95 (s, 1H) 7.64 (s, 1H) 7.48-7.54 (m, 1H) 7.29-7.35 (m, 1H)7.22-7.28 (m, 1H) 7.13-7.22 (m, 3H) 4.58 (d, J=7.12 Hz, 2H) 3.86 (d,J=11.53, 2.37 Hz, 2H) 3.20-3.30 (m, 2H) 2.11-2.24 (m, 1H) 1.45-1.54 (m,2H) 1.33-1.44 (m, 2H). MS (ESI+) m/z 422.1 (M+H)⁺.

Example 147(2-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone

The title compound was prepared according to the procedure outlined inExample 119B substituting 2-chlorobenzoyl chloride for benzoyl chlorideand Example 80A for benzyl azide. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.08(s, 1H) 7.99 (s, 1H) 7.75 (s, 1H) 7.66 (t, J=1.86 Hz, 1H) 7.56 (d,J=7.80 Hz, 1H) 7.47-7.53 (m, 1H) 7.36-7.42 (m, 1H) 7.23-7.34 (m, 2H)4.45 (d, J=6.78 Hz, 2H) 3.82 (d, J=11.19, 2.37 Hz, 2H) 3.18-3.29 (m, 2H)2.09-2.23 (m, 1H) 1.41-1.53 (m, 2H) 1.28-1.38 (m, 2H). MS (ESI+) m/z422.1 (M+H)⁺.

Example 148cyclopentyl[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone

The title compound was prepared according to the procedure outlined inExample 119B substituting cyclopentanecarbonyl chloride for benzoylchloride and Example 80A for benzyl azide. ¹H NMR (300 MHz, DMSO-d₆) δppm 13.27 (s, 1H) 8.18 (s, 1H) 7.95 (s, 1H) 7.68 (d, J=8.48 Hz, 1H) 7.52(d, J=8.48, 1.70 Hz, 1H) 4.47 (d, J=7.12 Hz, 2H) 3.85 (d, J=11.53, 2.37Hz, 2H) 3.18-3.30 (m, 2H) 3.02-3.14 (m, 1H) 2.00-2.17 (m, 1H) 1.19-1.76(m, 12H). MS (ESI+) m/z 380.1 (M+H)⁺.

Example 149 1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxylicAcid Example 149A Methyl1-benzyl-4-(tributylstannyl)-1H-1,2,3-triazole-5-carboxylate

Methyl propiolate (5.75 g, 68.4 mmol) was added to methylethyl(tributylstannyl)carbamate (26.9 g, 68.6 mmol) in a large sealedtube. The mixture was heated to 70° C. overnight. The mixture was cooledto ambient temperature and the vial was stirred unsealed for 10 minutes.Benzyl azide (10.2 mL, 81.6 mmol) was added, and the vial was resealedand heated to 130° C. overnight. The mixture was purified by silica gelchromatography eluting with a gradient of 5-40% ethyl acetate in hexanesto afford the title compound. MS (ESI+) m/z 508.3 (M+H)⁺.

Example 149B Methyl4-(1-acetyl-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazole-5-carboxylate

Example 149A (7.17 g, 14.1 mmol), Example 87A (4.02 g, 14.1 mmol),dichlorobis(triphenylphosphine)palladium(II) (1.01 mg, 1.44 mmol), andcopper thiophene-2-carboxylate (4.07 mg, 21.3 mmol) were combined intoluene (55 mL) in a large sealed tube under an inert atmosphere ofnitrogen. The tube was sealed and heated at 150° C. for 30 minutes. Themixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 10-50% ethyl acetate inhexanes to afford the title compound. MS (ESI+) m/z 376.1 (M+H)⁺.

Example 149C 1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxylicAcid

Example 149B (3.40 mg, 9.06 mmol) was dissolved in tetrahydrofuran (100mL), methanol (10 mL), and water (10 mL), and potassium hydroxide (1.63g, 29.1 mmol) was added. The mixture was stirred for 3 hours, wasdiluted with ethyl acetate and washed with 1 N hydrochloric acid, washedwith brine, and the combined organic layers were dried over sodiumsulfate. After filtration, the solvents were removed under reducedpressure to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm13.16 (s, 1H) 8.11-8.18 (m, 2H) 7.66-7.76 (m, 1H) 7.54-7.62 (m, 1H)7.31-7.43 (m, 3H) 7.22-7.29 (m, 2H) 5.93 (s, 2H). MS (ESI+) m/z 320.0(M+H)⁺.

Example 1505-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amineExample 150A 1-(Azidomethyl)-4-(trifluoromethyl)benzene

Sodium azide (2.30 g, 35.4 mmol) was added to a solution of4-(trifluoromethyl)benzyl bromide (4.26 g, 17.8 mmol) dissolved indimethyl sulfoxide (15 mL) and stirred at ambient temperature overnight.The mixture was diluted with ethyl acetate, washed with water and brine,and dried over sodium sulfate. After filtration, the solvent was removedunder reduced pressure to afford the title compound. The crude productwas used in the next step without further characterization.

Example 150B5-(4-Fluorophenyl)-4-(tributylstannyl)-1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazole

4-Fluorophenyl acetylene (524 mg, 4.36 mmol) was added to1,1,1-tributyl-N,N-dimethylstannanamine (1.46 g, 4.37 mmol), and themixture was stirred in a sealed vial at 50° C. for 30 minutes. Themixture was cooled to ambient temperature, and the vial was stirredunsealed for 10 minutes. Example 150A (1.28 g, 6.30 mmol) was added andthe vial was resealed and heated to 130° C. overnight. The mixture waspurified by silica gel chromatography eluting with a gradient of 5-35%ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z612.3 (M+H)⁺.

Example 150C2-Fluoro-5-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)benzonitrile

Example 150B (485 mg, 0.795 mmol), 5-bromo-2-fluorobenzonitrile (143 mg,0.715 mmol), dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.070mmol), and copper thiophene-2-carboxylate (205 mg, 1.08 mmol) werecombined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere ofnitrogen. The vial was sealed and heated at 150° C. for 30 minutes. Themixture was absorbed onto silica gel and purified by silica gelchromatography eluting with a gradient of 10-50% ethyl acetate inhexanes to afford the title compound. MS (ESI+) m/z 441.2 (M+H)⁺.

Example 150D5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine

Example 150C was treated with hydrazine hydrate (1.0 mL) in ethanol (1.0mL), and the reaction mixture was stirred and heated to 65° C. for 3hours. The mixture was diluted with methylene chloride and washed withwater. The organic layer was absorbed on silica gel and purified bysilica gel chromatography eluting with a gradient of 0-6% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 11.42 (s, 1H) 8.04 (s, 1H) 7.67 (d, J=8.14 Hz, 2H) 7.26-7.41 (m,4H) 7.22 (d, J=8.48 Hz, 2H) 7.03-7.15 (m, 2H) 5.62 (s, 2H) 5.36 (s, 2H).MS (ESI+) m/z 453.1 (M+H)⁺.

Example 1515-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amineExample 151A1-Benzyl-5-(4-fluorophenyl)-4-(tributylstannyl)-1H-1,2,3-triazole

4-Fluorophenyl acetylene (525 mg, 4.37 mmol) was added to1,1,1-tributyl-N,N-dimethylstannanamine (1.46 g, 4.37 mmol), and themixture was stirred in a sealed vial at 50° C. for 2 hours. The mixturewas cooled to ambient temperature, and the vial was stirred unsealed for10 minutes. Benzyl azide (850 μL, 6.80 mmol) was added, and the vial wasresealed and heated to 130° C. overnight. The mixture was purified bysilica gel chromatography eluting with a gradient of 5-35% ethyl acetatein hexanes to afford the title compound. MS (ESI+) m/z 544.4 (M+H)⁺.

Example 151B5-(1-Benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

Example 151A (361 mg, 0.666 mmol), 5-bromo-2-fluorobenzonitrile (119 mg,0.595 mmol), dichlorobis(triphenylphosphine)palladium(II) (45 mg, 0.064mmol), and copper thiophene-2-carboxylate (193 mg, 1.01 mmol) werecombined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere ofnitrogen. The vial was sealed and heated 150° C. for 30 minutes. Themixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 10-50% ethyl acetate inhexanes to afford the title compound. MS (ESI+) m/z 373.0 (M+H)⁺.

Example 151C5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

Example 151B (135 mg, 0.363 mmol) was treated with hydrazine hydrate(1.0 mL) in ethanol (1.0 mL) and stirred and heated to 65° C. for 3hours. The mixture was diluted with methylene chloride and washed withwater. The organic layer was absorbed on silica gel and purified bysilica gel chromatography eluting with a gradient of 0-6% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 11.40 (s, 1H) 8.02 (s, 1H) 7.24-7.38 (m, 7H) 7.03-7.14 (m, 2H)6.98 (d, J=7.29, 2.20 Hz, 2H) 5.50 (s, 2H) 5.35 (s, 2H). MS (ESI+) m/z385.1 (M+H)⁺.

Example 152[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl](tetrahydro-2H-pyran-4-yl)methanone

The title compound was prepared according to the procedure outlined inExample 119B substituting Example 80A for benzyl azide andtetrahydro-2H-pyran-4-carbonyl chloride for benzoyl chloride. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.30 (s, 1H) 8.18 (s, 1H) 8.00 (s, 1H) 7.69(d, J=8.48 Hz, 1H) 7.53 (d, J=8.65, 1.53 Hz, 1H) 4.48 (d, J=7.12 Hz, 2H)3.79-3.90 (m, 2H) 3.62-3.74 (m, 2H) 3.18-3.30 (m, 2H) 2.76-2.88 (m, 1H)2.64-2.76 (m, 2H) 2.00-2.17 (m, 1H) 1.20-1.58 (m, 8H). MS (ESI+) m/z396.0 (M+H)⁺.

Example 1535-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazoleExample 153A 1-Benzyl-5-o-tolyl-4-(tributylstannyl)-1H-1,2,3-triazole

2-Ethynyl toluene (456 μL, 3.62 mmol) was added to1,1,1-tributyl-N,N-dimethylstannanamine (1.21 g, 3.62 mmol), and themixture was stirred in a sealed vial at 70° C. for 3 hours. The mixturewas cooled to ambient temperature, and the vial was stirred unsealed for10 minutes. Benzyl azide (678 μL, 5.42 mmol) was added, and the vial wasresealed and heated to 130° C. overnight. The mixture was purified bysilica gel chromatography eluting with a gradient of 5-45% ethyl acetatein hexanes to afford the title compound. MS (ESI+) m/z 539.8 (M+H)⁺.

Example 153B1-(5-(1-Benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl)-1H-indazol-1-yl)ethanone

Example 153A (119 mg, 0.221 mmol), Example 87A (63 mg, 0.221 mmol),dichlorobis(triphenylphosphine)palladium(II) (16 mg, 0.023 mmol), andcopper thiophene-2-carboxylate (65 mg, 0.341 mmol) were combined intoluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen.The vial was sealed and heated at 150° C. for 20 minutes. The mixturewas absorbed on silica gel and purified by silica gel chromatographyeluting with a gradient 5-45% of ethyl acetate in hexanes to afford thetitle compound. MS (ESI+) m/z 408.7 (M+H)⁺.

Example 153C5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

Example 153B (42 mg, 0.103 mmol) was dissolved in tetrahydrofuran (2.0mL) and water (0.3 mL), and potassium hydroxide (48 mg, 0.856 mmol) wasadded. The mixture was stirred for 1 hour, was diluted with methylenechloride and washed with water. The organic layer was absorbed on silicagel and purified by silica gel chromatography eluting with a gradient of1-6% methanol in dichloromethane to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.07 (s, 1H) 7.97 (s, 1H) 7.73 (s, 1H)7.44-7.53 (m, 3H) 7.39 (t, J=6.95 Hz, 1H) 7.28-7.35 (m, 2H) 7.21-7.29(m, 3H) 6.86-6.95 (m, 2H) 5.28-5.45 (m, 2H) 1.59 (s, 3H). MS (ESI+) m/z366.1 (M+H)⁺.

Example 1545-{1-benzyl-5-[(4-methylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting Example 149C for Example 81A and 1-methylpiperazine for piperidine and tetrahydrofuran for dimethylformamide. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.20 (s, 1H) 8.16 (s, 1H) 7.96 (s, 1H)7.57-7.69 (m, 2H) 7.31-7.44 (m, 3H) 7.23-7.30 (m, 2H) 5.36-5.83 (m, 2H)3.40-3.65 (m, J=4.75 Hz, 2H) 2.38-2.49 (m, 2H) 2.10-2.22 (m, 2H) 1.89(s, 3H) 1.40 (t, J=4.92 Hz, 2H). MS (ESI+) m/z 402.2 (M+H)⁺.

Example 1551-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-ol

The title compound was prepared according to the procedure outlined inExample 81B substituting Example 149C for Example 81A and 4-hydroxypiperidine for piperidine and tetrahydrofuran for dimethylformamide. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.15-13.24 (m, 1H) 8.16 (s, 1H) 7.97 (s,1H) 7.55-7.68 (m, 2H) 7.32-7.43 (m, 3H) 7.23-7.30 (m, 2H) 5.41-5.83 (m,J=65.10 Hz, 2H) 4.58 (d, J=3.39 Hz, 1H) 3.74-3.91 (m, 1H) 3.37-3.48 (m,2H) 2.66-2.79 (m, 1H) 2.25-2.47 (m, 1H) 1.54-1.68 (m, 1H) 1.20-1.36 (m,1H) 0.74-0.90 (m, 1H) 0.40-0.60 (m, 1H). MS (ESI+) m/z 403.1 (M+H)⁺.

Example 1561-acetyl-5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazoleExample 156A5-(4-Fluorophenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-4-(tributylstannyl)-1H-1,2,3-triazole

4-Fluorophenyl acetylene (440 μL, 3.88 mmol) was added to1,1,1-tributyl-N,N-dimethylstannanamine (1.30 g, 3.89 mmol), and themixture was stirred in a sealed vial at 50° C. for 40 minutes. Themixture was cooled to ambient temperature, and the vial was stirredunsealed for 10 minutes. Example 80A (710 μL, 5.68 mmol) was added andthe vial was resealed and heated to 130° C. overnight. The mixture waspurified by silica gel chromatography eluting with a gradient of 5-50%ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z552.4 (M+H)⁺.

Example 156B1-acetyl-5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

Example 156A (433 mg, 0.787 mmol), Example 87A (205 mg, 0.717 mmol),dichlorobis(triphenylphosphine)palladium(II) (55 mg, 0.078 mmol), andcopper thiophene-2-carboxylate (224 mg, 1.17 mmol) were combined intoluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen.The vial was sealed and heated to 150° C. for 20 minutes. The mixturewas absorbed on silica gel and purified by silica gel chromatographyeluting with a gradient of 5-45% ethyl acetate in hexanes, and wastriturated with methanol to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.40-8.48 (m, J=0.68 Hz, 1H) 8.25 (d, J=8.82 Hz, 1H)7.82-7.91 (m, 1H) 7.73 (d, J=8.48, 1.70 Hz, 1H) 7.50-7.60 (m, 2H)7.38-7.49 (m, 2H) 4.13 (d, J=7.12 Hz, 2H) 3.76 (d, J=11.36, 2.54 Hz, 2H)3.10-3.25 (m, 2H) 2.70 (s, 3H) 1.86-2.08 (m, 1H) 1.37 (d, J=12.55, 1.70Hz, 2H) 1.03-1.23 (m, 2H). MS (ESI+) m/z 420.2 (M+H)⁺.

Example 1571-benzyl-4-(1H-indazol-5-yl)-N,N-dimethyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting Example 149C for Example 81A and dimethylaminefor piperidine and tetrahydrofuran for dimethylformamide. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.19 (s, 1H) 8.15 (s, 1H) 7.96 (t, J=1.19 Hz, 1H)7.62 (d, J=1.36 Hz, 2H) 7.33-7.44 (m, 3H) 7.24-7.33 (m, 2H) 5.59 (s, 2H)2.92 (s, 3H) 2.21 (s, 3H). MS (ESI+) m/z 347.1 (M+H)⁺.

Example 158N,1-dibenzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting Example 149C for Example 81A and benzyl aminefor piperidine and tetrahydrofuran for dimethylformamide. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.15 (s, 1H) 9.35 (t, J=6.10 Hz, 1H) 8.01 (d,J=12.55 Hz, 2H) 7.68 (d, J=8.82, 1.36 Hz, 1H) 7.53 (d, J=8.82 Hz, 1H)7.17-7.41 (m, 10H) 5.66 (s, 2H) 4.41 (d, J=6.10 Hz, 2H). MS (ESI+) m/z409.1 (M+H)⁺.

Example 159N-(2-hydroxy-2-phenylethyl)-5-(1H-indazol-5-yl)-N-methylisoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting DL-alpha-(methylaminomethyl)benzyl alcohol forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.01 (s, 1H) 8.29 (s, 1H)8.17 (s, 1H) 7.73-7.85 (m, 1H) 7.62-7.72 (m, 1H) 7.16-7.43 (m, 5H) 6.86(s, 1H) 5.17 (d, J=4.39 Hz, 1H) 4.89 (s, 1H) 3.71 (d, J=5.49 Hz, 2H)3.10 (s, 3H). MS (ESI+) m/z 363.1 (M+H)⁺.

Example 160N-[(1S)-2-hydroxy-1-phenylethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (S)-2-amino-2-phenylethanol for piperidine. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.37 (s, 1H) 9.05 (d, J=8.14 Hz, 1H) 8.40(s, 1H) 8.23 (s, 1H) 7.89 (d, J=8.65, 1.53 Hz, 1H) 7.70 (d, J=8.82 Hz,1H) 7.20-7.46 (m, 6H) 5.02-5.13 (m, 1H) 4.98 (t, J=5.59 Hz, 1H)3.61-3.82 (m, 2H). MS (ESI+) m/z 349.0 (M+H)⁺.

Example 161N-benzyl-N-(2-hydroxyethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 2-(benzylamino)ethanol for piperidine. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.37 (s, 1H) 9.05 (d, J=8.48 Hz, 1H) 8.40 (s,1H) 8.23 (s, 1H) 7.89 (d, J=8.65, 1.53 Hz, 1H) 7.70 (d, J=8.82 Hz, 1H)7.22-7.45 (m, 6H) 5.02-5.14 (m, 1H) 4.98 (t, J=5.76 Hz, 1H) 3.61-3.81(m, 2H). MS (ESI+) m/z 349.0 (M+H)⁺.

Example 1625-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-3-methyl-1H-indazoleExample 162A 1-(5-Bromo-3-methyl-1H-indazol-1-yl)ethanone

5-Bromo-3-methyl-1H-indazole (838 mg, 3.97 mmol) was dissolved inmethylene chloride (15 mL) and diisopropylethylamine (0.7 mL). Aceticanhydride (500 μL, 5.29 mmol) was added and the mixture was stirred atambient temperature overnight. The mixture was diluted with ethylacetate, washed with 1 N sodium hydroxide followed by 1 N hydrochloricacid and then brine. The organic layer was dried over sodium sulfate andthe solvent was removed under reduced pressure to afford the titlecompound. MS (ESI+) m/z 252.7 (M+H)⁺.

Example 162B1-(5-(1-Benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl)-3-methyl-1H-indazol-1-yl)ethanone

Example 153A (436 mg, 0.808 mmol), Example 162A (205 mg, 0.810 mmol),dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.080 mmol), andcopper thiophene-2-carboxylate (239 mg, 1.25 mmol) were combined intoluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen.The vial was sealed and heated 150° C. for 30 minutes. The mixture wasabsorbed on silica gel and purified by silica gel chromatography elutingwith a gradient of 10-50% ethyl acetate in hexanes to afford the titlecompound. MS (ESI+) m/z 422.6 (M+H)⁺.

Example 162C5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-3-methyl-1H-indazole

Example 162B (202 mg, 0.548 mmol) was dissolved in tetrahydrofuran (5.0mL), methanol (0.5 mL) and water (0.5 mL) and potassium hydroxide (133mg, 2.37 mmol) was added. The mixture was stirred for 1 hour and thenwas diluted with methylene chloride and washed with water. The organiclayer was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 30-80% ethyl acetate inhexanes to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm12.63 (s, 1H) 7.70 (s, 1H) 7.44-7.52 (m, 1H) 7.38-7.43 (m, 1H) 7.29-7.38(m, 4H) 7.22-7.29 (m, 3H) 6.89-6.96 (m, J=6.44, 3.05 Hz, 2H) 5.30-5.48(m, 2H) 2.32 (s, 3H) 1.58 (s, 3H). MS (ESI+) m/z 380.1 (M+H)⁺.

Example 1635-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amineExample 163A5-(1-Benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

Example 153A (450 mg, 0.834 mmol), 5-bromo-2-fluorobenzonitrile (167 mg,0.835 mmol), dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.080mmol), and copper thiophene-2-carboxylate (242 mg, 1.27 mmol) werecombined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere ofnitrogen. The vial was sealed and heated at 150° C. for 30 minutes. Themixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 10-50% ethyl acetate inhexanes to afford the title compound. MS (ESI+) m/z 369.2 (M+H)⁺.

Example 163B5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

Example 163A (202 mg, 0.548 mmol) was treated with hydrazine hydrate(1.0 mL) in ethanol (1.0 mL) and stirred and heated to 60° C. overnight.The mixture was diluted with methylene chloride and washed with water.The organic layer was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 35-85% ethyl acetate inhexanes to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.38 (s, 1H) 8.11 (s, 1H) 7.41-7.49 (m, 1H) 7.33-7.40 (m, J=6.95, 6.95Hz, 1H) 7.28-7.32 (m, 2H) 7.21-7.28 (m, 3H) 7.00-7.06 (m, 1H) 6.86-6.95(m, 3H) 5.27-5.44 (m, 4H) 1.58 (s, 3H). MS (ESI+) m/z 381.1 (M+H)⁺.

Example 1642-{2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]ethyl}-1H-isoindole-1,3(2H)-dione

The title compound was prepared according to the procedure outlined inExample 88 substituting 2-(but-3-ynyl)isoindoline-1,3-dione for3-phenyl-1-propyne. The crude product was subjected to 25%TFA/dichloromethane and purified by reverse-phase HPLC using anacetonitrile/water 0.1% TFA gradient elution method to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.33 (s, 1H) 8.65 (s, 1H)8.22 (s, 1H) 8.18 (d, J=1.53 Hz, 1H) 7.78-7.90 (m, 5H) 7.71-7.75 (m, 1H)3.92 (t, J=7.21 Hz, 2H) 3.08 (t, J=7.21 Hz, 2H). MS (ESI+) m/z 359.0(M+H)⁺.

Example 1655-{4-[(2,4-dichlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting 2,4-dichloro-1-(prop-2-ynyloxy)benzene for3-phenyl-1-propyne. The crude product was subjected to 25%TFA/dichloromethane and was purified by reverse-phase HPLC using anacetonitrile/water 0.1% TFA gradient elution method to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.38 (s, 1H) 8.93 (s, 1H)8.28 (d, J=1.53 Hz, 1H) 8.23 (s, 1H) 7.88 (d, J=8.90, 1.84 Hz, 1H) 7.76(d, J=8.90 Hz, 1H) 7.59 (d, J=2.46 Hz, 1H) 7.39-7.49 (m, 2H) 5.37 (s,2H). MS (ESI+) m/z 359.9 (M+H)⁺.

Example 1665-{4-[(2,6-dichlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting 1,3-dichloro-2-(prop-2-ynyloxy)benzene for3-phenyl-1-propyne. The crude product was subjected to 25%TFA/dichloromethane and purified by reverse-phase HPLC using anacetonitrile/water 0.1% TFA gradient elution method to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.39 (s, 1H) 8.97 (s, 1H)8.29 (d, J=1.53 Hz, 1H) 8.24 (s, 1H) 7.89 (d, J=9.00, 1.98 Hz, 1H) 7.76(d, J=8.85 Hz, 1H) 7.51-7.55 (m, 2H) 7.19-7.26 (m, J=8.24, 8.24 Hz, 1H)5.23 (s, 2H). MS (ESI+) m/z 359.9 (M+H)⁺.

Example 1675-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

Example 156B (168 mg, 0.401 mmol) was dissolved in tetrahydrofuran (5.0mL), methanol (0.5 mL) and water (0.5 mL) and potassium hydroxide (138mg, 2.46 mmol) was added. The mixture was stirred for 1 hour, and wasdiluted with methylene chloride and washed with water. The organic layerwas absorbed on silica gel and purified by silica gel chromatographyeluting with a gradient of 0-7% methanol in dichloromethane to affordthe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.08 (s, 1H) 8.02(s, 1H) 7.77 (s, 1H) 7.50-7.58 (m, 2H) 7.37-7.49 (m, 4H) 4.11 (d, J=7.12Hz, 2H) 3.76 (d, J=11.53, 2.71 Hz, 2H) 3.11-3.24 (m, 2H) 1.88-2.03 (m,1H) 1.30-1.43 (m, J=12.72, 1.86 Hz, 2H) 1.04-1.22 (m, 2H). MS (ESI+) m/z378.1 (M+H)⁺.

Example 1681-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indazoleExample 168A 1-(Prop-2-ynyl)-1H-indazole

Indazole (530 mg, 4.49 mmol) was dissolved in dimethylformamide (4 mL).Sodium hydride (60% suspension in mineral oil, 231 mg, 5.78 mmol) wasadded slowly, and the mixture was stirred for 10 minutes. Propargylbromide (80% wt in toluene, 5.0 mL) was added, and the mixture wasstirred at ambient temperature overnight. The mixture was diluted withethyl acetate, washed excessively with water, absorbed on silica gel,and purified by silica gel chromatography eluting with a gradient of5-30% ethyl acetate in hexanes to afford the title compound. MS (ESI+)m/z 157.1 (M+H)⁺.

Example 168B1-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 88 substituting Example 168A for 3-phenyl-1-propyne. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 8.78 (s, 1H) 8.22 (d, J=2.03, 0.68 Hz,1H) 8.20 (s, 1H) 8.10 (d, J=1.02 Hz, 1H) 7.80-7.87 (m, 2H) 7.75-7.80 (m,1H) 7.68-7.74 (m, 1H) 7.39-7.46 (m, 1H) 7.13-7.19 (m, 1H) 5.81 (s, 2H).MS (ESI+) m/z 316.0 (M+H)⁺.

Example 1695-[1-benzyl-5-(piperidin-1-ylcarbonyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting Example 149C for Example 81A andtetrahydrofuran for dimethylformamide. ¹H NMR (300 MHz, DMSO-d₆) δ ppm13.20 (s, 1H) 8.16 (s, 1H) 7.95-8.00 (m, J=1.02 Hz, 1H) 7.62-7.68 (m,1H) 7.57-7.63 (m, 1H) 7.31-7.44 (m, 3H) 7.24-7.30 (m, 2H) 5.36-5.84 (m,J=69.17 Hz, 2H) 3.43-3.59 (m, 2H) 2.43-2.59 (m, 2H) 1.17-1.46 (m,J=39.67 Hz, 4H) 0.49-0.65 (m, 2H). MS (ESI+) m/z 387.1 (M+H)⁺.

Example 1705-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazoleExample 170A1-((Tetrahydro-2H-pyran-4-yl)methyl)-5-o-tolyl-4-(tributylstannyl)-1H-1,2,3-triazole

2-Ethynyl toluene (576 mg, 4.57 mmol) was added to1,1,1-tributyl-N,N-dimethylstannanamine (1.53 g, 4.58 mmol), and themixture stirred in a sealed vial at 70° C. for 2 hours. The mixture wascooled to ambient temperature, and the vial was stirred unsealed for 10minutes. Example 80A (648 mg, 4.59 mmol) was added and the vial wasresealed and heated to 130° C. overnight. The mixture was purified bysilica gel chromatography eluting with a gradient of 5-50% ethyl acetatein hexanes to afford the title compound. MS (ESI+) m/z 548.4 (M+H)⁺.

Example 170B1-(5-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-5-o-tolyl-1H-1,2,3-triazol-4-yl)-1H-indazol-1-yl)ethanone

Example 170A (432 mg, 0.791 mmol), Example 87A (222 mg, 0.776 mmol),dichlorobis(triphenylphosphine)palladium(II) (58 mg, 0.083 mmol), andcopper thiophene-2-carboxylate (231 mg, 1.21 mmol) were combined intoluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen.The vial was sealed and heated at 150° C. for 20 minutes. The mixturewas absorbed on silica gel and purified by silica gel chromatographyeluting with a gradient of 20-70% ethyl acetate in hexanes to afford thetitle compound. MS (ESI+) m/z 416.2 (M+H)⁺.

Example 170C5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

Example 170B (184 mg, 0.443 mmol) was dissolved in tetrahydrofuran (3.0mL), methanol (0.3 mL), and water (0.3 mL) and potassium hydroxide (140mg, 2.50 mmol) was added. The mixture was stirred for 3 hours, and wasdiluted with methylene chloride and washed with water. The organic layerwas absorbed on silica gel and purified by silica gel chromatographyeluting with a gradient of 35-100% ethyl acetate in hexanes to affordthe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.08 (s, 1H) 7.98(s, 1H) 7.68-7.74 (m, J=1.02, 1.02 Hz, 1H) 7.49-7.56 (m, 1H) 7.45-7.49(m, 3H) 7.41-7.45 (m, J=7.46 Hz, 2H) 4.10 (d, J=13.73, 6.95 Hz, 1H) 3.89(d, J=13.90, 7.80 Hz, 1H) 3.77 (d, J=10.51, 2.71 Hz, 2H) 3.10-3.24 (m,2H) 1.92 (s, 3H) 1.88-1.98 (m, 1H) 1.26-1.43 (m, 2H) 1.04-1.21 (m, 2H).MS (ESI+) m/z 374.1 (M+H)⁺.

Example 1715-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amineExample 171A2-Fluoro-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)-5-o-tolyl-1H-1,2,3-triazol-4-yl)benzonitrile

Example 170A (411 mg, 0.752 mmol), 5-bromo-2-fluorobenzonitrile (151 mg,0.755 mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg, 0.074mmol), and copper thiophene-2-carboxylate (223 mg, 1.17 mmol) werecombined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere ofnitrogen. The vial was sealed and heated 150° C. for 30 minutes. Themixture was absorbed on silica gel and purified by silica gelchromatography eluting with a gradient of 10-50% ethyl acetate inhexanes to afford the title compound. MS (ESI+) m/z 377.6 (M+H)⁺.

Example 171B5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

Example 171A (175 mg, 0.465 mmol) was treated with hydrazine hydrate(2.0 mL) in ethanol (2.0 mL), and the mixture was stirred and heated to65° C. for 2 hours. The mixture was diluted with methylene chloride andwashed with water. The organic layer was absorbed on silica gel andpurified by silica gel chromatography eluting with a gradient of 1-8%methanol in dichloromethane to afford the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 11.39 (s, 1H) 8.08 (s, 1H) 7.45-7.55 (m, 1H)7.37-7.45 (m, 3H) 7.01-7.08 (m, J=8.48 Hz, 1H) 6.89-6.97 (m, 1H) 5.34(s, 2H) 4.09 (d, J=13.73, 6.95 Hz, 1H) 3.89 (d, J=13.73, 7.63 Hz, 1H)3.70-3.81 (m, 2H) 3.08-3.24 (m, 2H) 1.91 (s, 3H) 1.84-1.99 (m, 1H)1.22-1.41 (m, 2H) 1.04-1.20 (m, 2H). MS (ESI+) m/z 389.1 (M+H)⁺.

Example 1725-[1-benzyl-5-(morpholin-4-ylcarbonyl)-1H-1,2,3-triazol-4-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting Example 149C for Example 81A, morpholine forpiperidine, and tetrahydrofuran for dimethylformamide. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 13.22 (s, 1H) 8.18 (s, 1H) 7.95-8.03 (m, 1H) 7.64-7.70(m, 1H) 7.57-7.64 (m, 1H) 7.33-7.45 (m, 3H) 7.24-7.31 (m, 2H) 5.76 (s,1H) 5.52 (s, 1H) 3.33-3.59 (m, 4H) 2.61-2.74 (m, 2H) 2.45-2.59 (m, 2H).MS (ESI+) m/z 389.1 (M+H)⁺.

Example 1735-[1-benzyl-5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

A vial under argon containing Example 125B (50 mg, 0.12 mmol),4-methoxyphenylboronic acid (20 mg, 0.13 mmol), PdCl₂(dppf)dichloromethane (10 mg, 0.01 mmol) and potassium carbonate (33 mg, 0.24mmol) in DME (2 mL) and water (0.2 mL) was capped and heated at 80° C.in a heater shaker for 48 hours. The solvent was evaporated underreduced pressure, and the product was purified by reverse-phase HPLCusing an acetonitrile/water 0.1% TFA gradient elution method to affordthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.85 (s, 1H) 8.18(s, 1H) 7.26-7.34 (m, 3H) 7.19-7.25 (m, 2H) 7.16-7.19 (m, 2H) 7.02 (t,J=8.13 Hz, 4H) 5.47 (s, 2H) 3.80 (s, 3H). MS (ESI+) m/z 397.1 (M+H)⁺.

Example 174N-[(1S)-1-benzyl-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (S)-(−)-2-amino-3-phenyl-1-propanol forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 8.47 (d,J=8.82 Hz, 1H) 8.38 (s, 1H) 8.22 (s, 1H) 7.87 (d, J=8.82, 1.70 Hz, 1H)7.69 (d, J=8.82 Hz, 1H) 7.23-7.31 (m, 3H) 7.22 (s, 1H) 7.12-7.21 (m, 1H)4.90 (t, J=5.59 Hz, 1H) 4.07-4.28 (m, 1H) 3.40-3.58 (m, 2H) 2.89-3.00(m, 1H) 2.75-2.86 (m, 1H). MS (ESI+) m/z 363.0 (M+H)⁺.

Example 175N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (1S,2R)-(−)-cis-1-amino-2-indanol forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.38 (s, 1H) 8.42 (s, 1H)8.24 (s, 1H) 8.16 (d, J=8.48 Hz, 1H) 7.91 (d, J=8.82, 1.70 Hz, 1H) 7.71(d, J=8.48 Hz, 1H) 7.45 (s, 1H) 7.16-7.32 (m, 4H) 5.36-5.47 (m, 2H)4.50-4.61 (m, 1H) 3.14 (d, J=15.43, 5.26 Hz, 1H) 2.90 (d, J=16.28, 1.70Hz, 1H). MS (ESI+) m/z 361.0 (M+H)⁺.

Example 1765-{3-[(3-phenylmorpholin-4-yl)carbonyl]isoxazol-5-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting 3-phenylmorpholine hydrochloride forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.38 (s, 1H) 8.32-8.46 (m,1H) 8.24 (s, 1H) 7.81-7.96 (m, 1H) 7.70 (d, J=8.82 Hz, 1H) 7.37-7.55 (m,4H) 7.26-7.37 (m, 2H) 5.34-5.71 (m, 1H) 4.51 (d, J=13.22 Hz, 1H)3.78-4.39 (m, 3H) 3.59 (t, J=11.36 Hz, 1H) 3.33-3.41 (m, 1H). MS (ESI+)m/z 375.0 (M+H)⁺.

Example 177 N-benzyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting benzylamine for piperidine. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 13.36 (s, 1H) 9.35 (t, J=6.27 Hz, 1H) 8.40 (s, 1H) 8.23(s, 1H) 7.89 (d, J=8.82, 1.70 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 7.33-7.40(m, 4H) 7.32 (s, 1H) 7.22-7.30 (m, 1H) 4.48 (d, J=6.10 Hz, 2H). MS(ESI+) m/z 319.0 (M+H)⁺.

Example 178((1S)-2-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol

The title compound was prepared according to the procedure outlined inExample 81B substituting(S)-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol forpiperidine. MS (ESI+) m/z 435.1 (M+H)⁺.

Example 179N-[(1R)-3-hydroxy-1-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (R)-3-amino-3-phenylpropanol for piperidine. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.37 (s, 1H) 9.24 (d, J=8.48 Hz, 1H) 8.39(s, 1H) 8.23 (s, 1H) 7.88 (d, J=8.82, 1.70 Hz, 1H) 7.69 (d, J=8.82 Hz,1H) 7.38-7.46 (m, 2H) 7.34 (t, J=7.46 Hz, 2H) 7.19-7.30 (m, 2H)5.09-5.27 (m, 1H) 4.62 (t, J=4.92 Hz, 1H) 3.37-3.52 (m, 2H) 2.00-2.16(m, 1H) 1.84-2.00 (m, 1H). MS (ESI+) m/z 363.1 (M+H)⁺.

Example 180N-[(1S)-3-hydroxy-1-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (S)-3-amino-3-phenylpropanol for piperidine. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 9.24 (d, J=8.14 Hz, 1H) 8.39(s, 1H) 8.22 (s, 1H) 7.88 (d, J=8.65, 1.53 Hz, 1H) 7.69 (d, J=8.81 Hz,1H) 7.37-7.45 (m, 2H) 7.29-7.37 (m, 2H) 7.19-7.29 (m, 2H) 5.08-5.30 (m,1H) 4.55-4.68 (m, 1H) 3.37-3.51 (m, 2H) 2.00-2.14 (m, 1H) 1.83-1.99 (m,1H). MS (ESI+) m/z 363.0 (M+H)⁺.

Example 181N-2,3-dihydro-1H-inden-1-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 1-aminoindane for piperidine. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 13.37 (s, 1H) 9.13 (d, J=8.14 Hz, 1H) 8.39 (s, 1H) 8.23(s, 1H) 7.89 (d, J=8.82, 1.36 Hz, 1H) 7.70 (d, J=8.82 Hz, 1H) 7.35 (s,1H) 7.15-7.32 (m, 4H) 5.55 (q, J=7.91 Hz, 1H) 2.95-3.08 (m, 1H)2.76-2.94 (m, 1H) 2.37-2.49 (m, 1H) 2.01-2.15 (m, 1H). MS (ESI+) m/z345.0 (M+H)⁺.

Example 182N-2,3-dihydro-1H-inden-2-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 2-aminoindane for piperidine. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 13.37 (s, 1H) 9.08 (d, J=7.46 Hz, 1H) 8.39 (s, 1H) 8.23(s, 1H) 7.89 (d, J=8.82, 1.70 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 7.31 (s,1H) 7.10-7.28 (m, 4H) 4.63-4.79 (m, 1H) 3.24 (d, J=15.77, 7.63 Hz, 2H)2.96-3.08 (m, 2H). MS (ESI+) m/z 345.0 (M+H)⁺.

Example 1835-(1H-indazol-5-yl)-N-(1-phenylpropyl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting alpha-ethylbenzylamine for piperidine. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.36 (s, 1H) 9.18 (d, J=8.82 Hz, 1H) 8.38 (s,1H) 8.22 (s, 1H) 7.88 (d, J=8.82, 1.36 Hz, 1H) 7.69 (d, J=8.48 Hz, 1H)7.39-7.48 (m, 2H) 7.34 (t, J=7.29 Hz, 2H) 7.19-7.29 (m, 2H) 4.84-5.00(m, 1H) 1.69-2.04 (m, 2H) 0.91 (t, J=7.29 Hz, 3H). MS (ESI+) m/z 347.1(M+H)⁺.

Example 1845-{1-benzyl-5-[3-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 173 substituting 3-(dimethylamino)phenylboronic acidfor 4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.52(s, 1H) 8.17 (s, 1H) 7.22-7.35 (m, 4H) 7.08-7.15 (m, 2H) 7.03 (d, J=6.71Hz, 2H) 6.82 (d, J=8.39, 2.29 Hz, 1H) 6.48-6.54 (m, 2H) 5.47 (s, 2H)2.78 (s, 6H). MS (ESI+) m/z 410.2 (M+H)⁺.

Example 1855-{1-benzyl-5-[4-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 173 substituting 4-(dimethylamino)phenylboronic acidfor 4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.65(s, 1H) 8.17 (s, 1H) 7.23-7.38 (m, 3H) 7.12-7.16 (m, 2H) 7.01-7.09 (m,4H) 6.74-6.78 (m, 2H) 5.45 (s, 2H) 2.95 (s, 6H). MS (ESI+) m/z 410.2(M+H)⁺.

Example 186N-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}acetamide

The title compound was prepared according to the procedure outlined inExample 173 substituting 3-acetamidophenylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.05 (s,1H) 8.14 (s, 1H) 7.69 (d, J=8.54 Hz, 1H) 7.54 (s, 1H) 7.41 (t, J=7.93Hz, 1H) 7.24-7.32 (m, 3H) 7.08-7.16 (m, 2H) 6.93-7.04 (m, 3H) 5.48 (s,2H) 2.01 (s, 3H). MS (ESI+) m/z 424.2 (M+H)⁺.

Example 187N-{4-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}acetamide

The title compound was prepared according to the procedure outlined inExample 173 substituting 4-acetamidophenylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.14 (s,1H) 8.07 (s, 1H) 7.66 (d, J=8.85 Hz, 2H) 7.24-7.32 (m, 3H) 7.18-7.22 (m,2H) 7.04-7.11 (m, 2H) 6.98-7.02 (m, 2H) 5.48 (s, 2H) 5.35 (s, 2H)2.04-2.10 (m, 3H). MS (ESI+) m/z 424.1 (M+H)⁺.

Example 1885-{1-benzyl-5-[3-(1H-pyrazol-1-yl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 173 substituting 3-(1H-pyrazol-1-yl)phenylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.40 (s,1H) 8.45 (d, J=2.75 Hz, 1H) 8.09 (s, 1H) 7.99 (d, J=8.24, 1.53 Hz, 1H)7.80-7.85 (m, 1H) 7.74 (d, J=1.83 Hz, 1H) 7.56 (t, J=7.93 Hz, 1H)7.20-7.30 (m, 3H) 7.06-7.16 (m, 3H) 6.98-7.04 (m, 2H) 6.53-6.54 (m, 1H)5.55 (s, 2H) 5.35 (s, 2H). MS (ESI+) m/z 433.2 (M+H)⁺.

Example 1895-[1-benzyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 173 substituting 1-methyl-1H-pyrazol-4-ylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.78 (s,1H) 8.11 (s, 1H) 7.87 (s, 1H) 7.43 (s, 1H) 7.27-7.41 (m, 4H) 7.24 (d,J=8.54 Hz, 1H) 7.05-7.11 (m, J=7.02 Hz, 2H) 5.54 (s, 2H) 3.86 (s, 3H).MS (ESI+) m/z 370.9 (M+H)⁺.

Example 1903-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]-N-phenylbenzamide

The title compound was prepared according to the procedure outlined inExample 173 substituting 3-(phenylcarbamoyl)phenylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.41 (s,1H) 10.22 (s, 1H) 8.07-8.12 (m, 2H) 7.95 (s, 1H) 7.73 (d, J=7.63 Hz, 2H)7.60 (t, J=7.78 Hz, 1H) 7.43 (d, J=7.63 Hz, 1H) 7.32-7.39 (m, 2H)7.21-7.30 (m, 3H) 7.05-7.15 (m, 3H) 7.00 (d, J=6.71 Hz, 2H) 5.54 (s, 2H)5.36 (s, 2H). MS (ESI+) m/z 486.2 (M+H)⁺.

Example 1913-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]-N-benzylbenzamide

The title compound was prepared according to the procedure outlined inExample 173 substituting 3-(benzylcarbamoyl)phenylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.41 (s,1H) 9.04 (t, J=5.95 Hz, 1H) 8.07 (s, 1H) 8.01 (d, J=7.93 Hz, 1H) 7.85(s, 1H) 7.56 (t, J=7.78 Hz, 1H) 7.41 (d, J=7.63 Hz, 1H) 7.21-7.35 (m,8H) 7.01-7.11 (m, 2H) 6.96 (d, J=7.32, 2.14 Hz, 2H) 5.52 (s, 2H) 5.35(s, 2H) 4.45 (d, J=5.80 Hz, 2H). MS (ESI+) m/z 500.2 (M+H)⁺.

Example 1925-[1-benzyl-5-(1-methyl-1H-indol-5-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 173 substituting 1-methyl-1H-indol-5-ylboronic acidfor 4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.35(s, 1H) 8.14 (s, 1H) 7.54 (d, J=8.54 Hz, 1H) 7.50 (d, J=1.53 Hz, 1H)7.42 (d, J=3.05 Hz, 1H) 7.24-7.33 (m, 3H) 6.97-7.05 (m, 5H) 6.44 (d,J=2.75 Hz, 1H) 5.46 (s, 2H) 5.33 (s, 2H) 3.83 (s, 3H). MS (ESI+) m/z420.1 (M+H)⁺.

Example 1935-[1-benzyl-5-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 173 substituting 3-methoxyphenylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.40 (s,1H) 8.08 (s, 1H) 7.34-7.40 (m, 1H) 7.24-7.32 (m, 3H) 7.03-7.11 (m, 3H)6.98-7.02 (m, 2H) 6.80-6.85 (m, 2H) 5.49 (s, 2H) 5.35 (s, 2H) 3.66 (s,3H). MS (ESI+) m/z 397.1 (M+H)⁺.

Example 1945-[1-benzyl-5-(3-morpholin-4-ylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

A vial under argon containing Example 125B (35 mg, 0.09 mmol),3-morpholinophenylboronic acid (21 mg, 0.09 mmol),PdCl₂(dppf)-dichloromethane (7 mg, 0.009 mmol) and potassium carbonate(24 mg, 0.18 mmol) in DME (1 mL) and water (0.1 mL) was capped andheated at 80° C. in a heater shaker for 3 days. The solvent wasevaporated under reduced pressure, and the product was purified byreverse-phase HPLC using an acetonitrile/water 0.1% TFA gradient elutionmethod to afford the title compound as a TFA salt. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.52 (s, 1H) 8.14 (s, 1H) 7.26-7.34 (m, 4H) 6.98-7.12(m, 5H) 6.67-6.75 (m, 2H) 5.47 (s, 2H) 3.57-3.73 (m, 4H) 2.91-3.03 (m,4H). MS (ESI+) m/z 452.2 (M+H)⁺.

Example 1955-[3-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)isoxazol-5-yl]-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting isoindoline for piperidine. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 13.38 (s, 1H) 8.43 (s, 1H) 8.25 (s, 1H) 7.93 (d, J=8.82,1.36 Hz, 1H) 7.71 (d, J=8.48 Hz, 1H) 7.30-7.47 (m, 5H) 5.18 (s, 2H) 4.92(s, 2H). MS (ESI+) m/z 331.0 (M+H)⁺.

Example 1965-{3-[(4-methyl-2-phenylpiperazin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting 1-methyl-3-phenylpiperazine for piperidine. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.12 (s, 1H) 8.28-8.36 (m, 1H) 8.18 (s,1H) 7.83 (d, J=8.79, 1.46 Hz, 1H) 7.67 (d, J=8.79 Hz, 1H) 7.48 (d,J=7.69 Hz, 2H) 7.30-7.40 (m, 2H) 7.21-7.29 (m, 1H) 7.14 (s, 1H)5.56-5.73 (m, J=5.86 Hz, 1H) 3.99-4.19 (m, J=8.42 Hz, 1H) 3.38-3.47 (m,1H) 3.05-3.21 (m, J=7.69 Hz, 1H) 2.80 (d, J=11.72 Hz, 1H) 2.41 (d,J=12.08, 4.39 Hz, 1H) 2.24 (s, 3H) 2.02-2.16 (m, 1H). MS (ESI+) m/z388.1 (M+H)⁺.

Example 1971-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-amineExample 197A tert-Butyl1-(1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carbonyl)piperidin-4-ylcarbamate

The title compound was prepared according to the procedure outlined inExample 81B substituting Example 149C for Example 81B and4-Boc-aminopiperidine for piperidine. MS (ESI+) m/z 502.3 (M+H)⁺.

Example 197B1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-amine

Example 197A (101 mg, 0.201 mmol) was dissolved in 4 M hydrochloric acidin dioxane (4 mL) and methanol (1 mL) and stirred at ambient temperaturefor 2 hours. The solvents were removed under reduced pressure to affordthe title compound as an HCl salt. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.18(s, 1H) 7.92-8.08 (m, J=1.36 Hz, 3H) 7.53-7.70 (m, 2H) 7.24-7.47 (m, 5H)5.40-5.73 (m, J=3.39 Hz, 2H) 4.34-4.63 (m, 1H) 3.44-3.53 (m, J=3.39 Hz,1H) 2.95-3.17 (m, 2H) 2.76-2.94 (m, J=11.02, 11.02 Hz, 1H) 1.87-2.03 (m,J=11.87 Hz, 1H) 1.30-1.52 (m, J=10.85 Hz, 2H) 0.66-0.91 (m, J=10.17 Hz,1H). MS (ESI+) m/z 402.2 (M+H)⁺.

Example 198N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamideExample 198A tert-butyl3-amino-5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazole-1-carboxylate

Example 102B (200 mg, 0.55 mmol) and N,N-dimethylpyridin-4-amine (5 mg,0.04 mmol) were dissolved in methylene chloride. The mixture was stirredat room temperature while a solution of di-tert-butyl dicarbonate (120mg, 0.55 mmol) in 5 mL methylene chloride was added dropwise. Thereaction mixture was allowed to stir at room temperature for 8 hours,was concentrated under vacuum, dissolved in methylene chloride (10 mL)and washed with dilute aqueous HCl solution (1 N, 10 mL) and saturatedNaHCO₃ aqueous solution (10 mL). The organic layer was concentrated andpurified by reverse phase-HPLC (CH₃CN/H₂O/NH₄OAc) to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.29 (s, 2H), 7.43-7.59 (m,3H), 7.23-7.38 (m, 6H), 6.98 (d, J=7.17, 2.39 Hz, 2H), 6.38 (s, 2H),5.52 (s, 2H), 1.55 (s, 9H). MS (ESI+) m/z 467 (M+H)⁺.

Example 198BN-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide

Example 198A (37.5 mg, 0.08 mmol) and pyridine (12.7 mg, 0.16 mmol) weredissolved in methylene chloride (2 mL). The mixture was allowed to stirat room temperature. Benzoyl chloride (14 mg, 0.1 mmol) was added to themixture. The reaction mixture was allowed to stir at room temperatureovernight, concentrated under vacuum and purified by reversephase-HPLC(CH₃CN/H₂O/NH₄OAc) to afford the Boc-protected precursor. Theprecursor was treated with 1:1 TFA/dichloromethane (2 mL) for 1 hour andwas concentrated under vacuum to afford the title compound as a TFAsalt. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.84 (s, 1H), 10.70 (s, 1H), 8.01(d, J=6.99 Hz, 2H), 7.87 (s, 1H), 7.50-7.69 (m, 3H), 7.36-7.48 (m, 5H),7.18-7.35 (m, 5H), 6.92-7.03 (m, 2H), 5.48 (s, 2H). MS (ESI+) m/z 471(M+H)⁺.

Example 199N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzenesulfonamide

The title compound was prepared according to the procedure outlined inExample 198B substituting benzenesulfonyl chloride for benzoyl chloride.¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.69 (s, 1H), 10.61 (s, 1H), 7.99 (s,1H), 7.70-7.76 (m, 2H), 7.45-7.62 (m, 6H), 7.24-7.36 (m, 7H), 6.99 (d,J=6.99, 2.21 Hz, 2H), 5.50 (s, 2H). MS (ESI+) m/z 507 (M+H)⁺.

Example 200N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-(4-methoxyphenyl)urea

Example 198A (25 mg, 0.54 mmol) was dissolved in dioxane (2 mL) and1-isocyanato-4-methoxybenzene (24 mg, 0.16 mmol) was added to thesolution. The reaction mixture was stirred at 80° C. for 12 hours,concentrated, and purified by reverse phase-HPLC (CH₃CN/H₂O/NH₄OAc) toafford the Boc-protected precursor. The precursor was treated with 1:1TFA/dichloromethane (2 mL) for 1 hour and concentrated under vacuum toafford the title compound as a TFA salt. ¹H NMR (300 MHz, DMSO-d₆) δ ppm12.54 (s, 1H), 9.51 (s, 1H), 9.42 (s, 1H), 8.28 (s, 1H), 7.45-7.51 (m,3H), 7.36-7.42 (m, 2H), 7.24-7.35 (m, 7H), 6.98 (d, J=7.17, 2.39 Hz,2H), 6.87-6.94 (m, 2H), 5.50 (s, 2H), 3.74 (s, 3H). MS (ESI+) m/z 516(M+H)⁺.

Example 201N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]butanamide

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 198B substituting butyryl chloride for benzoylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.77-10.84 (m, 1H), 8.07 (s,1H), 7.97 (d, J=8.82 Hz, 1H), 7.64 (d, J=8.82, 1.47 Hz, 1H), 7.43-7.57(m, 3H), 7.22-7.38 (m, 5H), 6.91-7.06 (m, 2H), 5.50 (s, 2H), 2.33 (t,J=7.17 Hz, 2H), 1.54-1.60 (m, 2H), 0.91 (t, J=7.35 Hz, 3H). MS (ESI+)m/z 437 (M+H)⁺.

Example 202N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-methylpropanamide

The title compound was prepared according to the procedure outlined inExample 198B substituting isobutyryl chloride for benzoyl chloride. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 12.66 (s, 1H), 10.12 (s, 1H), 7.80 (s, 1H),7.42-7.55 (m, 4H), 7.33-7.39 (m, 1H), 7.22-7.32 (m, 5H), 6.97 (d,J=6.99, 2.57 Hz, 2H), 5.48 (s, 1H), 2.59-2.69 (m, 1H), 1.07 (d, J=6.99Hz, 6H). MS (ESI+) m/z 437 (M+H)⁺.

Example 203N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]cyclopropanecarboxamide

The title compound was prepared according to the procedure outlined inExample 198B substituting cyclopropanecarbonyl chloride for benzoylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.45-10.64 (s, 1H), 7.91 (s,1H), 7.43-7.55 (m, 3H), 7.31-7.43 (m, 2H), 7.23-7.30 (m, 5H), 6.97 (d,J=7.17, 2.39 Hz, 2H), 5.48 (s, 2H), 1.77-1.91 (m, 1H), 0.69-0.87 (m,4H). MS (ESI+) m/z 435 (M+H)⁺.

Example 204N-[1-benzoyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide

Example 89B (33 mg, 0.1 mmol) was dissolved in tetrahydrofuran (0.6 mL)in a CEM microwave tube. Benzoyl chloride (28 mg, 0.2 mmol) was addedand the mixture was heated at 120° C. for 15 minutes in the CEM-Discovermicrowave. The reaction mixture was cooled to room temperature, andconcentrated. The residue was purified by reversephase-HPLC(CH₃CN/H₂O/NH₄OAc) to afford the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 11.35 (s, 1H), 8.55 (d, J=8.82 Hz, 1H), 8.36 (s,1H), 8.17 (d, J=8.64, 1.65 Hz, 1H), 8.06 (d, J=7.54, 2.39 Hz, 4H),7.51-7.72 (m, 6H), 7.26-7.45 (m, 5H), 5.71 (s, 2H), 1.76-1.87 (m, 1H),1.11 (d, J=6.62 Hz, 2H), 0.44 (d, J=4.41 Hz, 2H). MS (ESI+) m/z 539(M+H)⁺.

Example 205N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-fluorobenzamideExample 205A tert-Butyl3-amino-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazole-1-carboxylate

The title compound was prepared according to the procedure outlined inExample 198A substituting Example 89B for Example 102A. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.26 (s, 1H), 7.96-8.07 (m, 1H), 7.86-7.95 (m, 1H),7.35-7.46 (m, 3H), 7.28-7.35 (m, 2H), 6.35-6.47 (m, 2H), 5.70 (s, 2H),1.72-1.84 (m, 1H), 1.60 (s, 9H), 0.99-1.10 (d, J=1.84 Hz, 2H), 0.38 (d,J=3.68 Hz, 2H). MS (ESI+) m/z 431 (M+H)⁺.

Example 205BN-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-fluorobenzamide

Example 205A (25 mg, 0.058 mmol) and pyridine (9.2 mg, 0.116 mmol) weredissolved in methylene chloride (1 mL). The mixture was allowed to stirat room temperature, and 3-fluorobenzoyl chloride (11.1 mg, 0.58 mmol)was added to the mixture. The reaction mixture was allowed to stir atroom temperature overnight, and was concentrated and purified by reversephase-HPLC(CH₃CN/H₂O/NH₄OAc) to afford the Boc-protected precursor. Theprecursor was treated with 1:1 TFA/dichloromethane (2 mL) for 1 hour andconcentrated under vacuum to afford the title compound as a TFA salt. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 10.58 (s, 1H), 7.75 (s, 1H), 7.51-7.60 (m,1H), 7.46 (d, J=8.82, 1.47 Hz, 1H), 7.15-7.28 (m, 2H), 7.10 (d, J=2.21Hz, 1H), 6.88-7.05 (m, 6H), 5.31 (s, 2H), 1.35-1.47 (m, J=5.15 Hz, 1H),0.68 (d, J=8.27, 1.65 Hz, 2H), 0.03 (d, J=5.52 Hz, 2H). MS (ESI+) m/z453 (M+H)⁺.

Example 206N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide

The title compound was prepared according to the procedure outlined inExample 205B substituting benzoyl chloride for 3-fluorobenzoyl chloride.¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.89 (s, 1H), 10.83 (s, 1H), 8.02-8.15(m, 3H), 7.83 (d, J=8.82, 1.47 Hz, 1H), 7.50-7.66 (m, 4H), 7.24-7.43 (m,5H), 5.67 (s, 2H), 1.77 (m, 1H), 0.99-1.10 (m, 2H), 0.39 (m, 2H). MS(ESI+) m/z 435 (M+H)⁺.

Example 207N-benzyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

To a solution of Example 89B (18.3 mg, 0.05 mmol) in dimethylformamide(2 mL) was added acetic acid (15 mg, 0.25 mmol) and benzaldehyde (6.4mg, 0.06 mmol). The reaction mixture was stirred at room temperatureovernight. Sodium triacetoxyborohydride (NaBH(OAc)₃, 32 mg, 0.15 mmol)was added to the mixture. The reaction was stirred at room temperaturefor 3 hours, concentrated and purified by reverse phase-HPLC(CH₃CN/H₂O/NH₄OAc) to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 13.09 (s, 1H), 9.24 (s, 1H), 8.02-8.10 (m, 3H), 7.84-7.90(m, 1H), 7.49-7.67 (m, 4H), 7.25-7.45 (m, 5H), 5.70 (s, 2H), 3.30 (s,2H), 1.88-1.95 (m, 1H), 1.01-1.09 (m, 2H), 0.43 (d, J=4.04 Hz, 2H). MS(ESI+) m/z 421 (M+H)⁺.

Example 208N-[(1R)-1-benzyl-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (R)-(+)-2-amino-3-phenyl-1-propanol (37 mg,0.245 mmol) for piperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.36 (s,1H) 8.46 (d, J=8.82 Hz, 1H) 8.37 (s, 1H) 8.22 (s, 1H) 7.87 (dd, J=8.82,1.36 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 7.12-7.35 (m, 6H) 4.89 (t, J=5.59Hz, 1H) 4.13-4.25 (m, 1H) 3.40-3.58 (m, 2H) 2.90-2.99 (m, 1H) 2.74-2.87(m, 1H). MS (ESI+) m/z 363.0 (M+H)⁺.

Example 209 5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazole Example 209A1-(5-Bromo-1H-indazol-1-yl)ethanone

4-Bromo-2-methylaniline (25.0 g, 134 mmol) was dissolved in chloroform(250 mL), and the mixture was cooled to 5° C. Acetic anhydride (35 mL,343 mmol) was added dropwise, and the mixture was allowed to warm toambient temperature. Potassium acetate (3.97 g, 40.4 mmol) andisoamylnitrite (35 mL, 262 mmol) were added, and the mixture was heatedat 70° C. overnight. The mixture was neutralized with saturated sodiumbicarbonate and extracted with methylene chloride. The combined organiclayers were concentrated under reduced pressure, and the resultingresidue was triturated with methanol to afford the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 8.45 (s, 1H) 8.26 (d, J=8.82 Hz, 1H) 8.17(d, J=1.70 Hz, 1H) 7.77 (dd, J=8.82, 2.03 Hz, 1H) 2.72 (s, 3H).

Example 209B 5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazole

Example 209A (425 mg, 1.78 mmol),1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(508 mg, 1.79 mmol), dichlorobis(triphenylphosphine)palladium(II) (133mg, 0.189 mmol), and potassium carbonate (742 mg, 5.37 mmol) werecombined in a sealed vial with dioxane (10 mL) and water (1 mL) underand inert atmosphere of nitrogen, and the mixture was heated to 110° C.overnight. The mixture was diluted with methylene chloride and washedwith water. The organic layer was absorbed on silica gel and purified bysilica gel chromatography eluting with a gradient of 45-90% ethylacetate in hexanes to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 13.00 (s, 1H) 8.25 (s, 1H) 8.02 (s, 1H) 7.92 (s, 2H)7.55-7.61 (m, 1H) 7.48-7.54 (m, 1H) 7.25-7.40 (m, 5H) 5.35 (s, 2H). MS(ESI+) m/z 274.9 (M+H)⁺.

Example 210N-[(1R)-3-hydroxy-1-phenylpropyl]-5-(3-methyl-1H-indazol-5-yl)isoxazole-3-carboxamideExample 210A tert-Butyl 5-bromo-3-methyl-1H-indazole-1-carboxylate

5-Bromo-3-methyl-1H-indazole (5.11 g, 24.2 mmol) and catalyticdimethylaminopyridine (˜30 mg) were dissolved in methylene chloride (100mL). Di-tert-butyl dicarbonate (5.9 g, 27.0 mmol) was added, and themixture was stirred at ambient temperature for 3 hours. The solvent wasremoved under reduced pressure, and the resulting residue was dilutedwith ethyl acetate and washed with 1 N sodium hydroxide (twice), 0.1 Nhydrochloric acid, and brine. The organic layer was dried over sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure to afford the title compound. MS (ESI+) m/z 210.8 (M−Boc)⁺.

Example 210B tert-Butyl3-methyl-5-((trimethylsilyl)ethynyl)-1H-indazole-1-carboxylate

Example 210A (7.55 g, 24.3 mmol),dichlorobis(triphenylphosphine)palladium(II) (870 mg, 1.24 mmol), andcopper(I) iodide (250 mg, 1.31 mmol) were combined in triethylamine (60mL) under an inert atmosphere of nitrogen. Trimethylsilyl acetylene (4.0mL, 28.9 mmol) was added, and the mixture was heated at 60° C.overnight. The mixture was diluted with methylene chloride and washedwith 0.1 M hydrochloric acid. The organic layer was absorbed onto silicagel and purified by silica gel chromatography eluting with a gradient of10-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+)m/z 228.9 (M−Boc)⁺.

Example 210C 5-Ethynyl-3-methyl-1H-indazole

Example 210B (7.26 g, 22.1 mmol) was dissolved in methanol (170 mL). Asolution of 1 N potassium hydroxide (45 mL) was added, and the mixturewas stirred at ambient temperature overnight. The solvent was removedunder reduced pressure, and the resulting residue was diluted with ethylacetate and washed with water and brine. The organic layer was driedover sodium sulfate and concentrated under reduced pressure to affordthe title compound. MS (ESI+) m/z 157.1 (M+H)⁺.

Example 210D Ethyl 5-(3-methyl-1H-indazol-5-yl)isoxazole-3-carboxylate

Example 210C (411 mg, 2.63 mmol) was dissolved in toluene (15 mL) andtriethylamine (478 μL) and warmed to 90° C. Ethyl chlorooximidoacetate(480 mg, 3.17 mmol) dissolved in toluene (15 mL) was added slowlydropwise over 30 minutes. Following the addition, the mixture wasdiluted with ethyl acetate and washed with 1 N hydrochloric acid. Theorganic layer was concentrated under reduced pressure and the resultingresidue was triturated with methanol to afford the title compound. MS(ESI+) m/z 271.9 (M+H)⁺.

Example 210E 5-(3-methyl-1H-indazol-5-yl)isoxazole-3-carboxylic Acid

Example 210D (325 mg, 1.20 mmol) was dissolved in tetrahydrofuran (10mL), methanol (1 mL), and water (1 mL) and potassium hydroxide (150 mg,2.67 mmol) was added. The mixture was stirred at ambient temperature for3 hours. The mixture was diluted with ethyl acetate and washed with 1 Nhydrochloric acid. The product precipitated in the separatory funnel andwas filtered to afford the title compound. MS (ESI+) m/z 243.9 (M+H)⁺.

Example 210FN-[(1R)-3-hydroxy-1-phenylpropyl]-5-(3-methyl-1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting Example 210E for Example 81A and(R)-3-amino-3-phenylpropan-1-ol for piperidine. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 12.93 (s, 1H) 8.45 (d, J=8.82 Hz, 1H) 8.33 (s, 1H) 7.84(d, J=8.82, 1.70 Hz, 1H) 7.59 (d, J=9.16 Hz, 1H) 7.21-7.29 (m, 5H)7.13-7.21 (m, 1H) 4.89 (t, J=5.59 Hz, 1H) 4.10-4.26 (m, 1H) 3.42-3.56(m, 2H) 2.88-3.00 (m, 1H) 2.75-2.87 (m, 1H) 2.55 (s, 3H). MS (ESI+) m/z377.1 (M+H)⁺.

Example 2113-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenol

A vial under argon containing Example 125B (35 mg, 0.09 mmol),3-hydroxyphenylboronic acid (12 mg, 0.09 mmol),PdCl₂(dppf)-dichloromethane (7 mg, 0.009 mmol) and potassium carbonate(24 mg, 0.18 mmol) in DME (1 mL) and water (0.1 mL) was capped andheated at 80° C. in a heater shaker for 3 days. The solvent wasevaporated and the product was purified by reverse-phase HPLC using anacetonitrile/water 0.1% TFA gradient elution method to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.40 (s, 1H) 9.68 (s, 1H)8.09 (s, 1H) 7.24-7.35 (m, 5H) 6.98-7.13 (m, 3H) 6.88 (d, J=8.09, 1.98Hz, 1H) 6.73 (s, 1H) 6.60-6.66 (m, 1H) 5.47 (s, 2H) 5.35 (s, 2H). MS(ESI+) m/z 383.1 (M+H)⁺.

Example 2123-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]benzamide

The title compound was prepared according to the procedure outlined inExample 173 substituting 3-carbamoylphenylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.41 (s,1H) 8.07 (s, 1H) 7.97-8.03 (m, 2H) 7.83-7.87 (m, 1H) 7.53 (t, J=7.78 Hz,1H) 7.45 (s, 1H) 7.38 (d, J=7.63 Hz, 1H) 7.23-7.30 (m, 3H) 7.00-7.10 (m,2H) 6.96 (d, J=7.48, 1.98 Hz, 2H) 5.51 (s, 2H) 5.35 (s, 2H). MS (ESI+)m/z 410.1 (M+H)⁺.

Example 2135-{1-benzyl-5-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 173 substituting 4-(methylsulfonyl)phenylboronic acid for4-methoxyphenylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.44 (s,1H) 7.94-8.01 (m, 3H) 7.58 (d, J=8.54 Hz, 2H) 7.22-7.30 (m, 3H)7.04-7.13 (m, 2H) 6.98 (d, J=7.48, 1.98 Hz, 2H) 5.56 (s, 2H) 5.37 (s,2H) 3.28 (s, 3H). MS (ESI+) m/z 445.2 (M+H)⁺.

Example 214N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-chlorobenzamide

The title compound was prepared according to the procedure outlined inExample 205B substituting 2-chlorobenzoyl chloride for 3-fluorobenzoylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.94 (s, 1H), 8.24 (s, 1H),7.85 (d, J=8.82, 1.47 Hz, 1H), 7.65 (d, J=6.99, 1.84 Hz, 1H), 7.43-7.61(m, 4H), 7.26-7.42 (m, 5H), 5.68 (s, 2H), 1.71-1.83 (m, 1H), 1.04-1.12(m, 2H), 0.37-0.45 (m, 2H). MS (ESI+) m/z 469 (M+H)⁺.

Example 215N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-4-chlorobenzamide

The title compound was prepared according to the procedure outlined inExample 205B substituting 4-chlorobenzoyl chloride for 3-fluorobenzoylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.53 (s, 1H), 7.65-7.71 (m,3H), 7.42 (d, J=8.82, 1.47 Hz, 1H), 7.18-7.24 (m, 2H), 7.12-7.18 (m,1H), 6.93-7.02 (m, 3H), 6.83-6.92 (m, 3H), 5.27 (s, 2H), 1.30-1.44 (m,1H), 0.59-0.67 (m, 2H), −0.07-0.04 (m, 2H). MS (ESI+) m/z 469 (M+H)⁺.

Example 216N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]ethanesulfonamide

The title compound was prepared according to the procedure outlined inExample 205B substituting ethanesulfonyl chloride for 3-fluorobenzoylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.19 (s, 1H), 8.15 (s, 1H),7.82 (d, J=8.64, 1.65 Hz, 1H), 7.53 (d, J=8.82 Hz, 1H), 7.35-7.45 (m,3H), 7.27-7.35 (m, 2H), 5.69 (s, 2H), 3.30 (q, J=7.35 Hz, 2H), 1.74-1.87(m, 1H), 1.27-1.36 (m, 3H), 1.02-1.12 (m, 2H), 0.34-0.44 (m, 2H). MS(ESI+) m/z 423 (M+H)⁺.

Example 217N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzenesulfonamide

The title compound was prepared according to the procedure outlined inExample 205B substituting benzenesulfonyl chloride for 3-fluorobenzoylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.75 (s, 1H), 10.69 (s, 1H),8.02 (s, 1H), 7.71-7.83 (m, 3H), 7.43-7.60 (m, 4H), 7.34-7.43 (m, 3H),7.27-7.34 (m, 2H), 5.69 (s, 2H), 1.69-1.83 (m, 1H), 0.99-1.11 (m, 2H),0.31-0.45 (m, 2H). MS (ESI+) m/z 471 (M+H)⁺.

Example 218N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-chlorobenzenesulfonamide

The title compound was prepared according to the procedure outlined inExample 205B substituting 2-chlorobenzene-1-sulfonyl chloride for3-fluorobenzoyl chloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.36 (s, 1H),10.60 (s, 1H), 7.67 (s, 1H), 7.62 (d, J=7.91, 1.65 Hz, 1H), 7.40 (d,J=8.82, 1.47 Hz, 1H), 7.14-7.27 (m, 2H), 7.00-7.12 (m, 4H), 6.96-7.00(m, 1H), 6.90-6.95 (m, 2H), 5.31 (s, 2H), 1.29-1.44 (m, 1H), 0.61-0.74(m, 2H), −0.05-0.05 (m, 2H). MS (ESI+) m/z 505 (M+H)⁺.

Example 219N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-chlorobenzenesulfonamide

The title compound was prepared as an HCl salt according to theprocedure outlined in Example 205B substituting3-chlorobenzene-1-sulfonyl chloride for 3-fluorobenzoyl chloride. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 12.84 (s, 1H), 10.86 (s, 1H), 8.00 (s, 1H),7.82 (s, 1H), 7.72 (d, J=7.72 Hz, 1H), 7.64 (d, J=1.84 Hz, 1H), 7.57 (d,J=7.72 Hz, 1H), 7.50 (d, J=8.82 Hz, 1H), 7.34-7.45 (m, 3H), 7.28-7.34(m, 2H), 5.69 (s, 2H), 1.71-1.83 (m, 1H), 1.06 (m, 2H), 0.37 (m, 2H). MS(ESI+) m/z 505 (M+H)⁺.

Example 220N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-4-chlorobenzenesulfonamide

The title compound was prepared as an HCl salt according to theprocedure outlined in Example 205B substituting4-chlorobenzene-1-sulfonyl chloride for 3-fluorobenzoyl chloride. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 12.80 (s, 1H), 10.79 (s, 1H), 8.00 (s, 1H),7.73-7.83 (m, 3H), 7.56-7.64 (m, 2H), 7.49 (d, J=8.82 Hz, 1H), 7.34-7.45(m, 3H), 7.28-7.34 (m, 2H), 5.69 (s, 2H), 1.71-1.86 (m, 1H), 0.99-1.12(m, 2H), 0.31-0.43 (m, 2H). MS (ESI+) m/z 505 (M+H)⁺.

Example 221N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2,5-dimethylfuran-3-sulfonamide

The title compound was prepared as an HCl salt according to theprocedure outlined in Example 205B substituting2,5-dimethylfuran-3-sulfonyl chloride for 3-fluorobenzoyl chloride. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 12.82 (s, 1H), 10.48 (s, 1H), 8.00 (s, 1H),7.78 (d, J=8.64, 1.65 Hz, 1H), 7.50 (d, J=9.19 Hz, 1H), 7.34-7.45 (m,3H), 7.28-7.33 (m, 2H), 6.20 (s, 1H), 5.69 (s, 2H), 2.11 (s, 6H),1.71-1.84 (m, 1H), 1.01-1.11 (m, 2H), 0.32-0.41 (m, 2H). MS (ESI+) m/z489 (M+H)⁺.

Example 2225-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-(2-chlorobenzyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 207 substituting 2-chlorobenzaldehyde for benzaldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 11.55 (s, 1H), 8.20 (s, 1H), 7.69 (d, J=8.46,1.47 Hz, 1H), 7.49 (d, J=8.82 Hz, 1H), 7.34-7.46 (m, 4H), 7.23-7.33 (m,5H), 5.69 (s, 2H), 4.56 (s, 2H), 1.72-1.83 (m, 1H), 0.99-1.09 (m, 2H),0.35-0.42 (m, 2H). MS (ESI+) m/z 455 (M+H)⁺.

Example 2235-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-(3-chlorobenzyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 207 substituting 3-chlorobenzaldehyde for benzaldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 11.53 (s, 1H), 8.15 (s, 1H), 7.59-7.77 (m, 1H),7.25-7.48 (m, 10H), 5.68 (s, 2H), 4.49 (s, 2H), 1.71-1.80 (m, 1H), 1.04(s, 2H), 0.38 (s, 2H).

Example 224N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-chlorobenzamide

The title compound was prepared according to the procedure outlined inExample 205B substituting 3-chlorobenzoyl chloride for 3-fluorobenzoylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.99 (s, 1H), 8.12 (s, 2H),8.03 (d, J=7.72 Hz, 1H), 7.83 (d, J=8.46 Hz, 1H), 7.68 (s, 1H), 7.58 (t,J=8.09 Hz, 2H), 7.33-7.44 (m, 3H), 7.25-7.33 (m, 2H), 5.68 (s, 2H),1.72-1.86 (m, 1H), 0.99-1.12 (m, 2H), 0.34-0.45 (m, 2H). MS (ESI+) m/z470 (M+H)⁺.

Example 225N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-furamide

The title compound was prepared according to the procedure outlined inExample 205B substituting furan-2-carbonyl chloride for 3-fluorobenzoylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.36 (s, 1H), 7.71 (s, 1H),7.42 (d, J=8.82, 1.47 Hz, 1H), 7.15 (d, J=8.82 Hz, 1H), 7.06 (d, J=3.31Hz, 1H), 6.93-7.03 (m, 3H), 6.86-6.93 (m, 2H), 6.31 (d, J=3.49, 1.65 Hz,1H), 5.28 (s, 1H), 1.31-1.45 (m, 1H), 0.59-0.71 (m, 2H), −0.05-0.05 (m,2H). MS (ESI+) m/z 425 (M+H)⁺.

Example 2265-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-ethyl-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 207 substituting acetaldehyde for benzaldehyde. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.56 (s, 1H), 8.30-8.42 (m, 1H), 7.90-8.17 (m, 2H),7.20-7.45 (m, 5H), 5.70 (s, 2H), 1.78-1.93 (m, 2H), 1.67 (s, 1H), 1.06(m, 3H), 0.95 (m, 2H), 0.29-0.48 (m, 2H). MS (ESI+) m/z 359 (M+H)⁺.

Example 2275-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-(4-chlorobenzyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 207 substituting 4-chlorobenzaldehyde for benzaldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 10.01 (s, 1H), 9.25 (s, 1H), 8.25-8.33 (m, 1H),8.09 (d, J=8.46 Hz, 1H), 7.84-7.97 (m, 2H), 7.57-7.73 (m, 2H), 7.26-7.51(m, 6H), 5.70 (s, 2H), 1.71-1.84 (m, 1H), 0.97-1.15 (m, 2H), 0.36-0.47(m, 2H). MS (ESI+) m/z 455 (M+H)⁺.

Example 2285-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-N-(3-furylmethyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 207 substituting furan-3-carbaldehyde for benzaldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 8.21 (s, 1H), 7.90 (s, 1H), 7.71-7.82 (m, 1H),7.55-7.68 (m, 2H), 7.24-7.51 (m, 6H), 5.68 (s, 2H), 4.33 (s, 2H),1.67-1.85 (m, 1H), 0.95-1.13 (m, 2H), 0.30-0.42 (m, 2H). MS (ESI+) m/z411 (M+H)⁺.

Example 229N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-[5-methyl-2-(trifluoromethyl)-3-furyl]urea

Example 205A (30 mg, 0.07 mmol) was dissolved in dioxane (2 mL) and3-isocyanato-5-methyl-2-(trifluoromethyl)furan (40 mg, 0.21 mmol) wasadded to the solution. The reaction mixture was stirred at 80° C. for 12hours, concentrated and purified by reverse phase-HPLC(CH₃CN/H₂O/NH₄OAc)to afford the Boc-protected precursor. The precursor was dissolved inmethanol and treated with excess HCl in dioxane (4 M, 0.5 mmol). Thereaction was allowed to stir for 5 hours and concentrated under vacuumto afford the title compound as an HCl salt. ¹H NMR (300 MHz, DMSO-d₆) δppm 12.73 (s, 1H), 10.19 (s, 1H), 8.40 (s, 1H), 7.83 (d, J=8.82, 1.47Hz, 1H), 7.64-7.75 (m, 1H), 7.49 (d, J=8.82 Hz, 1H), 7.35-7.45 (m, 3H),7.27-7.35 (m, 2H), 5.69 (s, 2H), 2.33 (s, 3H), 1.73-1.84 (m, 1H),1.02-1.11 (m, 2H), 0.35-0.43 (m, 2H). MS (ESI+) m/z 522 (M+H)⁺.

Example 230N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-furamide

The title compound was prepared as an HCl salt according to theprocedure outlined in Example 205B substituting furan-3-carbonylchloride for 3-fluorobenzoyl chloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.64 (s, 1H), 8.46 (s, 1H), 8.13 (s, 1H), 7.74-7.84 (m, 2H), 7.52-7.58(m, 1H), 7.33-7.46 (m, 3H), 7.24-7.33 (m, 3H), 7.06 (s, 1H), 5.68 (s,2H), 1.70-1.86 (m, 1H), 0.99-1.09 (m, 2H), 0.33-0.44 (m, 2H). MS (ESI+)m/z 425 (M+H)⁺.

Example 2315-(1H-indazol-5-yl)-N-[(1S)-1-phenylpropyl]isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (S)-(−)-1-phenylpropyl amine for piperidine. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.37 (s, 1H) 9.20 (d, J=8.48 Hz, 1H) 8.39(s, 1H) 8.23 (s, 1H) 7.88 (d, J=8.81, 1.70 Hz, 1H) 7.69 (d, J=8.81 Hz,1H) 7.38-7.49 (m, 2H) 7.18-7.38 (m, 4H) 4.83-5.02 (m, 1H) 1.73-1.97 (m,2H) 0.86-0.97 (m, 3H). MS (ESI+) m/z 347.0 (M+H)⁺.

Example 2325-(1H-indazol-5-yl)-N-[(1R)-1-phenylpropyl]isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (R)-(−)-1-phenylpropyl amine for piperidine. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.37 (s, 1H) 9.20 (d, J=8.48 Hz, 1H) 8.39(s, 1H) 8.23 (s, 1H) 7.88 (d, J=8.65, 1.53 Hz, 1H) 7.69 (d, J=8.81 Hz,1H) 7.39-7.48 (m, 2H) 7.18-7.38 (m, 4H) 4.85-4.99 (m, 1H) 1.74-1.97 (m,2H) 0.91 (t, J=7.29 Hz, 3H). MS (ESI+) m/z 347.0 (M+H)⁺.

Example 233 5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-amine Example 233A5-(1-Benzyl-1H-pyrazol-4-yl)-2-fluorobenzonitrile

5-Bromo-2-fluorobenzonitrile (484 mg, 2.42 mmol),1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(736 mg, 2.59 mmol), dichlorobis(triphenylphosphine)palladium(II) (174mg, 0.248 mmol), and potassium carbonate (1.36 g, 9.84 mmol) werecombined in a sealed vial with dioxane (10 mL) and water (1 mL) under aninert atmosphere of nitrogen, and the mixture was heated to 110° C.overnight. The mixture was diluted with methylene chloride and washedwith water. The organic layer was absorbed on silica gel and purified bysilica gel chromatography eluting with a gradient of 10-50% ethylacetate in hexanes to afford the title compound. MS (ESI+) m/z 290.0(M+H)⁺.

Example 233B 5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-amine

Example 233A (591 mg, 2.13 mmol) was treated with hydrazine hydrate (4.0mL) in ethanol (3.0 mL) and was stirred and heated to 70° C. overnight.The mixture was diluted with methylene chloride and washed with water.The organic layer was concentrated under reduced pressure, and theresulting residue was triturated with methanol to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.32 (s, 1H) 8.10 (s, 1H)7.85 (s, 1H) 7.80 (s, 1H) 7.44 (d, J=8.48, 1.70 Hz, 1H) 7.25-7.41 (m,5H) 7.21 (d, J=8.82 Hz, 1H) 5.35 (s, 2H) 5.24-5.30 (m, 2H). MS (ESI+)m/z 290.0 (M+H)⁺.

Example 2341-benzyl-4-(1H-indazol-5-yl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-triazole-5-carboxamide

Into a 20 mL vial, a solution of Example 149C (51 mg, 0.16 mmol)dissolved in dimethylformamide (0.5 mL) was added, followed by theaddition of (S)-(+)-tetrahydrofurfurylamine (18.2 mg, 0.18 mmol)dissolved in dimethylformamide (0.9 mL). A solution of HATU (68 mg, 0.18mmol) dissolved in dimethylformamide (0.5 mL) was added followed by asolution of diisopropylethylamine (0.087 mL, 0.5 mmol) dissolved indimethylformamide (0.5 mL). The mixture was shaken at 50° C. overnight.The reaction was filtered through a Si-Carbonate cartridge (6 mL-1 g)supplied by Silicycle Chemical Division, and the filtrate wastransferred to 20 mL vials. The reaction was checked by LC/MS andconcentrated to dryness. The residue was dissolved in 1:1 DMSO/methanoland purified by reverse phase HPLC (Agilent, 5%-100% TFA/water gradient,8 minute run). ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm 1.35-1.54 (m, 1H)1.64-1.96 (m, 3H) 3.17-3.26 (m, 1H) 3.32-3.38 (m, 1H) 3.50-3.77 (m, 2H)3.81-4.00 (m, 1H) 5.58-5.74 (m, 2H) 7.21-7.41 (m, 5H) 7.54-7.66 (m, 1H)7.68-7.84 (m, 1H) 8.01-8.19 (m, 2H). MS (ESI−) m/z 401 (M−H)⁻.

Example 2351-benzyl-4-(1H-indazol-5-yl)-N-(2-isopropoxyethyl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting 2-aminoethylisopropyl ether for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm0.98 (d, 6H) 3.31-3.45 (m, 4H) 3.45-3.57 (m, 1H) 5.61-5.74 (m, 2H)7.25-7.46 (m, 5H) 7.57-7.65 (m, 1H) 7.68-7.80 (m, 1H) 8.04-8.13 (m, 2H).MS (ESI+) m/z 405 (M+H)⁺.

Example 2361-benzyl-4-(1H-indazol-5-yl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting (R)-(−)-tetrahydrofurfurylamine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm1.34-1.60 (m, 1H) 1.65-1.94 (m, 3H) 3.16-3.26 (m, 1H) 3.33-3.39 (m, 1H)3.51-3.77 (m, 2H) 3.78-4.00 (m, 1H) 5.60-5.73 (m, 2H) 7.26-7.45 (m, 5H)7.56-7.68 (m, 1H) 7.71-7.79 (m, 1H) 8.01-8.15 (m, 2H). MS (ESI−) m/z 401(M−H)⁻.

Example 2371-benzyl-4-(1H-indazol-5-yl)-N-(tetrahydrofuran-3-ylmethyl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting 3-aminomethyltetrahydrofuran for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm1.36-1.59 (m, 1H) 1.67-2.00 (m, 1H) 2.19-2.45 (m, 1H) 3.11-3.23 (m, 2H)3.45-3.77 (m, 2H) 5.45-6.14 (m, 2H) 7.16-7.44 (m, 5H) 7.50-7.84 (m, 2H)7.96-8.25 (m, 2H). MS (ESI+) m/z 403 (M+H)⁺.

Example 2381-benzyl-N-cyclopentyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting cyclopentylamine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm1.19-1.63 (m, 6H) 1.71-1.99 (m, 2H) 3.99-4.37 (m, 1H) 5.52-5.77 (m, 2H)7.22-7.45 (m, 5H) 7.55-7.83 (m, 2H) 7.95-8.20 (m, 2H). MS (ESI−) m/z 385(M−H)⁻.

Example 2391-benzyl-N-(cyclopentylmethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting aminomethylcyclopentane for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm1.02-1.28 (m, 2H) 1.34-1.73 (m, 6H) 1.83-2.17 (m, 1H) 3.03-3.17 (m, 2H)5.51-5.80 (m, 2H) 7.20-7.42 (m, 5H) 7.52-7.81 (m, 2H) 7.93-8.19 (m, 2H).MS (ESI+) m/z 401 (M+H)⁺.

Example 2401-benzyl-N-ethyl-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting N-methylethylamine hydrochloride for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm0.33-0.56 (m, 1H) 0.90-1.14 (m, 2H) 2.15-2.25 (m, 2H) 2.58-2.69 (m, 1H)2.82-3.01 (m, 1H) 3.35-3.52 (m, 1H) 5.40-5.67 (m, 2H) 7.14-7.48 (m, 5H)7.56-7.79 (m, 2H) 7.90-8.24 (m, 2H). MS (ESI+) m/z 361 (M+H)⁺.

Example 2411-benzyl-4-(1H-indazol-5-yl)-N-isopropyl-N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting methylisopropylamine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm0.22-0.51 (m, 2H) 0.84-1.09 (m, 4H) 1.96-2.13 (m, 2H) 2.74-2.87 (m, 1H)4.44-4.92 (m, 1H) 5.43-5.67 (m, 2H) 7.20-7.44 (m, 5H) 7.51-7.73 (m, 2H)7.84-8.14 (m, 2H). MS (ESI+) m/z 375 (M+H)⁺.

Example 2421-benzyl-4-(1H-indazol-5-yl)-N-(2-methoxyethyl)-N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting N-(2-methoxyethyl)methylamine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm2.25-2.42 (m, 2H) 2.74-3.06 (m, 4H) 3.40-3.75 (m, 3H) 5.38-5.73 (m, 2H)7.18-7.45 (m, 5H) 7.53-7.74 (m, 2H) 7.85-8.19 (m, 2H). MS (ESI+) m/z 391(M+H)⁺.

Example 2431-benzyl-4-(1H-indazol-5-yl)-N-phenyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting aniline for (S)-(+)-tetrahydrofurfurylamine. ¹HNMR (300 MHz, DMSO-d₆/D₂O) δ ppm 5.65-5.79 (m, 2H) 7.04-7.55 (m, 10H)7.54-7.84 (m, 2H) 7.95-8.21 (m, 2H). MS (ESI+) m/z 395 (M+H)⁺.

Example 2441-benzyl-N-(4-chlorophenyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting 4-chloroaniline for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm5.70-5.74 (m, 2H) 7.25-7.42 (m, 7H) 7.43-7.52 (m, 2H) 7.54-7.66 (m, 1H)7.68-7.77 (m, 1H) 8.03-8.15 (m, 2H). MS (ESI−) m/z 427 (M−H)⁻.

Example 2451-benzyl-4-(1H-indazol-5-yl)-N-(2-morpholin-4-ylethyl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting N-(3-aminopropyl)morpholine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm2.94-3.13 (m, 6H) 3.46-3.61 (m, 2H) 3.63-3.79 (m, 4H) 5.61-5.88 (m, 2H)7.19-7.46 (m, 5H) 7.56-7.88 (m, 2H) 7.88-8.30 (m, 2H). MS (ESI−) m/z 430(M−H)⁻.

Example 2461-benzyl-N-[2-(dimethylamino)ethyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 234 substituting N,N,N-trimethylethylenediamine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm2.28-2.42 (m, 3H) 2.73-3.00 (m, 6H) 3.07-3.19 (m, 2H) 3.56-3.80 (m, 2H)5.55-5.68 (m, 2H) 7.24-7.47 (m, 5H) 7.56-7.78 (m, 2H) 7.91-8.02 (m, 1H)8.10-8.17 (m, 1H). MS (ESI+) m/z 404 (M+H)⁺.

Example 2471-benzyl-N-(2-hydroxyethyl)-4-(1H-indazol-5-yl)-N-propyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting 2-(propylamino)ethanol for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm0.22-0.39 (m, 1H) 0.80-1.06 (m, 3H) 1.50-1.75 (m, 1H) 2.65-2.78 (m, 1H)2.80-2.94 (m, 1H) 2.97-3.09 (m, 1H) 3.37-3.50 (m, 1H) 3.51-3.63 (m, 1H)3.61-3.73 (m, 1H) 5.39-5.74 (m, 2H) 7.20-7.44 (m, 5H) 7.50-7.85 (m, 2H)7.86-8.25 (m, 2H). MS (ESI+) m/z 405 (M+H)⁺.

Example 2481-benzyl-N-[3-(dimethylamino)propyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 234 substituting N,N,N-trimethyl-1,3-propanediaminefor (s)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm8.06-8.23 (m, 1H) 7.85-8.05 (m, 1H) 7.57-7.73 (m, 2H) 7.19-7.48 (m, 5H)5.41-5.74 (m, 2H) 3.36-3.45 (m, 2H) 2.88-3.10 (m, 3H) 2.60-2.86 (m, 5H)2.24-2.42 (m, 4H) 1.73-1.91 (m, 1H). MS (ESI+) m/z 418 (M+H)⁺.

Example 2491-benzyl-N-[2-(diethylamino)ethyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 234 substituting N,N-diethyl-N-methylethylenediaminefor (s)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.82-8.24 (m, 2H) 7.56-7.76 (m, 2H) 7.15-7.49 (m, 5H) 5.54-5.71 (m, 2H)3.60-3.77 (m, 2H) 3.20-3.24 (m, 2H) 3.13-3.18 (m, 2H) 3.03-3.11 (m, 2H)2.32-2.44 (m, 3H) 0.63-1.41 (m, 6H). MS (ESI+) m/z 432 (M+H)⁺.

Example 250N,1-dibenzyl-N-ethyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting N-ethylbenzylamine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.81-8.20 (m, 2H) 7.49-7.71 (m, 2H) 7.24-7.51 (m, 9H) 6.39-7.18 (m, 2H)5.41-5.74 (m, 2H) 4.53-4.84 (m, 1H) 3.82-4.00 (m, 1H) 3.37-3.54 (m, 1H)2.61-2.78 (m, 1H) 0.91-1.08 (m, 1H) 0.27-0.45 (m, 2H). MS (ESI+) m/z 437(M+H)⁺.

Example 251N,1-dibenzyl-N-(2-hydroxyethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting N-benzylethanolamine for(S)-(+)-tetrahydrofurfurylamine. MS (ESI+) m/z 453 (M+H)⁺.

Example 252(3R)-1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-3-ol

The title compound was prepared according to the procedure outlined inExample 234 substituting (R)-(+)-3-hydroxypiperidine hydrochloride for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.83-8.22 (m, 2H) 7.51-7.78 (m, 2H) 7.23-7.45 (m, 5H) 5.46-5.75 (m, 2H)3.80-4.31 (m, 1H) 3.40-3.68 (m, 1H) 2.58-3.15 (m, 2H) 2.19-2.49 (m, 1H)0.31-2.14 (m, 4H). MS (ESI+) m/z 403 (M+H)⁺.

Example 2531-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidine-4-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting isonipecotamide for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.86-8.24 (m, 2H) 7.53-7.70 (m, 2H) 7.22-7.46 (m, 5H) 5.42-5.77 (m, 2H)4.19-4.48 (m, 1H) 2.65-3.10 (m, 2H) 2.27-2.47 (m, 1H) 2.05-2.24 (m, 1H)1.65-1.89 (m, 1H) 1.29-1.55 (m, 1H) 0.98-1.27 (m, 1H) 0.52-0.87 (m, 1H).MS (ESI+) m/z 430 (M+H)⁺.

Example 2545-{1-benzyl-5-[(2,6-dimethylmorpholin-4-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 234 substituting 2,6-dimethylmorpholine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.87-8.27 (m, 2H) 7.50-7.76 (m, 2H) 7.12-7.45 (m, 5H) 5.46-5.68 (m, 2H)4.16-4.43 (m, 1H) 2.61-2.98 (m, 1H) 2.16-2.41 (m, 2H) 1.77-2.13 (m, 1H)0.86-1.39 (m, 3H) 0.38-0.83 (m, 3H). MS (ESI+) m/z 417 (M+H)⁺.

Example 2555-{5-[(4-acetylpiperazin-1-yl)carbonyl]-1-benzyl-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 234 substituting 1-acetylpiperazine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.89-8.41 (m, 2H) 7.55-7.86 (m, 2H) 7.07-7.51 (m, 5H) 5.44-5.82 (m, 2H)3.46-3.70 (m, 3H) 3.35-3.49 (m, 2H) 2.57-2.93 (m, 3H) 1.61-2.03 (m, 3H).MS (ESI+) m/z 430 (M+H)⁺.

Example 2565-{1-benzyl-5-[(4-phenylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 234 substituting 1-phenylpiperazine for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.79-8.38 (m, 2H) 7.53-7.73 (m, 2H) 7.22-7.46 (m, 5H) 7.05-7.19 (m, 2H)6.64-6.79 (m, 3H) 5.54-5.68 (m, 2H) 3.50-3.90 (m, 2H) 2.93-3.15 (m, 2H)2.62-2.89 (m, 2H) 2.19-2.43 (m, 2H). MS (ESI−) m/z 462 (M−H)⁻.

Example 2571-benzyl-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting (R)-(+)-2-amino-3-methyl-1-butanol for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.95-8.31 (m, 2H) 7.52-7.96 (m, 2H) 7.18-7.46 (m, 5H) 5.42-5.86 (m, 2H)3.68-3.94 (m, 1H) 3.38-3.59 (m, 2H) 1.49-2.08 (m, 1H) 0.50-1.20 (m, 6H).MS (ESI+) m/z 405 (M+H)⁺.

Example 2581-benzyl-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting (S)-(−)-2-amino-3-methyl-1-butanol for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm7.94-8.36 (m, 2H) 7.52-7.84 (m, 2H) 7.18-7.51 (m, 5H) 5.57-5.76 (m, 2H)3.75-3.94 (m, 1H) 3.35-3.54 (m, 2H) 1.70-1.94 (m, 1H) 0.54-1.09 (m, 6H).MS (ESI+) m/z 405 (M+H)⁺.

Example 2591-benzyl-N-[3-(1H-imidazol-1-yl)propyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined inExample 234 substituting 1-(3-aminopropyl)imidazole for(S)-(+)-tetrahydrofurfurylamine. ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ ppm8.57-8.85 (m, 1H) 7.92-8.16 (m, 2H) 7.60-7.80 (m, 2H) 7.47-7.55 (m, 2H)7.19-7.40 (m, 5H) 5.54-5.75 (m, 2H) 3.83-4.21 (m, 2H) 3.19-3.26 (m, 2H)1.79-2.06 (m, 2H). MS (ESI+) m/z 427 (M+H)⁺.

Example 260N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-ethylurea

The title compound was prepared as a hydrochloric acid salt according tothe procedure outlined in Example 229 substituting isocyanatoethane for3-isocyanato-5-methyl-2-(trifluoromethyl)furan. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 12.38 (s, 1H), 9.47 (s, 1H), 8.38 (s, 1H), 7.85-7.97 (m,1H), 7.78 (d, J=8.82, 1.47 Hz, 1H), 7.34-7.50 (m, 4H), 7.24-7.33 (m,2H), 5.69 (s, 2H), 3.17-3.29 (m, 2H), 1.70-1.83 (m, 1H), 1.12 (t, J=7.17Hz, 3H), 1.00-1.08 (m, 2H), 0.37 (d, J=3.68 Hz, 2H). MS (ESI+) m/z 402(M+H)⁺.

Example 261N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-phenylurea

The title compound was prepared as a hydrochloric acid salt according tothe procedure outlined in Example 229 substituting isocyanatobenzene for3-isocyanato-5-methyl-2-(trifluoromethyl)furan. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 12.47-12.78 (m, 1H), 9.64 (s, 1H), 8.39 (s, 1H),7.70-7.95 (m, 1H), 7.45-7.60 (m, 3H), 7.27-7.45 (m, 7H), 7.02 (m, 1H),5.69 (s, 2H), 1.79 (m, 1H), 1.07 (m, 2H), 0.40 (m, 2H). MS (ESI+) m/z450 (M+H)⁺.

Example 262N-benzyl-N′-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]urea

The title compound was prepared as a hydrochloric acid salt according tothe procedure outlined in Example 229 substituting(isocyanatomethyl)benzene for3-isocyanato-5-methyl-2-(trifluoromethyl)furan. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 12.42 (s, 1H), 9.61 (s, 1H), 8.37 (s, 1H), 8.23-8.33 (m,1H), 7.79 (d, J=8.82, 1.47 Hz, 1H), 7.36-7.50 (m, 4H), 7.28-7.36 (m,6H), 7.21-7.27 (m, 1H), 5.69 (s, 2H), 4.45 (d, J=5.88 Hz, 2H), 1.65-1.79(t, J=8.27, 8.27 Hz, 1H), 0.99-1.08 (m, 2H), 0.30-0.43 (m, 2H). MS(ESI+) m/z 464 (M+H)⁺.

Example 263N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-(2-chlorophenyl)urea

The title compound was prepared as a hydrochloric acid salt according tothe procedure outlined in Example 229 substituting1-chloro-2-isocyanatobenzene for3-isocyanato-5-methyl-2-(trifluoromethyl)furan. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 12.74 (s, 1H), 10.23 (s, 1H), 8.44 (s, 1H), 8.34 (d,J=8.09 Hz, 1H), 7.83 (d, J=8.82, 1.47 Hz, 1H), 7.46-7.55 (m, 2H),7.35-7.45 (m, 3H), 7.28-7.35 (m, 3H), 7.03-7.12 (m, 1H), 5.70 (s, 2H),1.70-1.86 (m, 1H), 1.00-1.12 (m, 2H), 0.33-0.45 (m, 2H). MS (ESI+) m/z484 (M+H)⁺.

Example 264N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-(3-chlorophenyl)urea

The title compound was prepared as a hydrochloric acid salt according tothe procedure outlined in Example 229 substituting1-chloro-3-isocyanatobenzene for3-isocyanato-5-methyl-2-(trifluoromethyl)furan. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 12.66 (s, 1H), 10.02 (s, 1H), 9.71 (s, 1H), 8.22-8.48 (m,1H), 7.71-7.91 (m, 2H), 7.51 (d, J=8.46 Hz, 1H), 7.37-7.46 (m, 2H),7.26-7.37 (m, 5H), 7.02-7.11 (m, 1H), 5.69 (s, 2H), 1.73-1.89 (m, 1H),0.99-1.11 (m, 2H), 0.33-0.48 (m, 2H). MS (ESI+) m/z 484 (M+H)⁺.

Example 265N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-(4-chlorophenyl)urea

The title compound was prepared as a hydrochloric acid salt according tothe procedure outlined in Example 229 substituting1-chloro-4-isocyanatobenzene for3-isocyanato-5-methyl-2-(trifluoromethyl)furan. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 12.65 (s, 1H), 9.96 (s, 1H), 9.68 (s, 1H), 8.37 (s, 1H),7.81 (d, J=8.82, 1.47 Hz, 1H), 7.53-7.60 (m, 2H), 7.50 (d, J=8.82 Hz,1H), 7.39-7.44 (m, 1H), 7.33-7.40 (m, 4H), 7.27-7.32 (m, 2H), 5.69 (s,2H), 1.71-1.87 (m, 1H), 1.00-1.12 (m, 2H), 0.34-0.44 (m, 2H). MS (ESI+)m/z 484 (M+H)⁺.

Example 266N-[5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamideExample 266A tert-butyl3-amino-5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazole-1-carboxylate

The title compound was prepared according to the procedure outlined inExample 198A substituting Example 125B for Example 102B. The product wasused directly in subsequent reactions without characterization.

Example 266BN-[5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide

The title compound was prepared as a TFA salt according to the procedureoutlined in Example 205B substituting Example 266A for Example 205A. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 12.97 (s, 1H), 10.89 (s, 1H), 8.28 (s, 1H),8.05-8.14 (m, 2H), 7.88 (d, J=8.82, 1.47 Hz, 1H), 7.58-7.67 (m, 2H),7.54 (t, J=7.35 Hz, 2H), 7.29-7.45 (m, 3H), 7.23 (d, J=6.99 Hz, 2H),5.73 (s, 2H). MS (ESI+) m/z 521 (M+H)⁺.

Example 2673-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanenitrile Example267A3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.00 g,25.8 mmol) in acetonitrile (50 mL) was added acrylonitrile (3.4 mL, 52mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.94 mL, 12.9mmol). After about 2 hours, the reaction mixture was concentrated underreduced pressure. The crude material was then dissolved in a minimalamount of dichloromethane and purified via silica gel chromatographyeluting with a gradient of 10-50% ethyl acetate in heptane to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.03 (s, 1H), 7.64 (s,1H), 4.40 (t, J=6.4 Hz, 2H), 3.06 (t, J=6.4 Hz, 2H), 1.26 (s, 12H). MS(ESI+) m/z 247.3 (M+H)⁺.

Example 267B3-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanenitrile

To a microwave vial was added 5-bromo-1H-indazol-3-amine (0.14 g, 0.66mmol), tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol),and sodium carbonate (0.147 g, 1.39 mmol) followed by a solution ofExample 267A (0.212 g, 0.858 mmol) in 1,2-dimethoxyethane (2.50 mL) andthen water (1.25 mL). The mixture was heated in a CEM microwave at about150° C. for about 20 minutes (275 psi maximum pressure, about 2 minutesramp, 200 maximum watts) and then the mixture was concentrated underreduced pressure. Methanol (20 mL) was added and the resulting mixturewas stirred for about 1 hour. The insoluble material was removed byfiltration. The filtrate was concentrated under reduced pressure ontosilica gel and purified via silica gel chromatography eluting with astepwise gradient of dichloromethane/methanol/ammonium hydroxide(990:9:1 to 985:13.5:1.5 to 980:18:2) to afford a solid. This solid wasdissolved in a minimum amount of hot acetonitrile (˜2 mL), filtered toremove minor amount of insolubles, while washing with methanol (<0.5mL), and left to sit at ambient temperature. The resulting solid thatformed overnight was collected by filtration, while washing withadditional acetonitrile, and dried in a vacuum oven at about 60° C. forabout 2 hours to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 11.35 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.44 (dd,J=8.54, 1.26 Hz, 1H), 7.23 (d, J=8.62 Hz, 1H), 5.32 (s, 2H), 4.42 (t,J=6.36 Hz, 2H), 3.10 (t, J=6.43 Hz, 2H). MS (ESI+) m/z 253.2 (M+H)⁺.

Example 268 2-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]acetamideExample 268A2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide

A suspension of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g,10.3 mmol), 2-bromoacetamide (2.14 g, 15.5 mmol), and potassiumcarbonate (2.14 g, 15.5 mmol) in acetone (60 mL) was heated at about 50°C. for about 3.5 days. The reaction mixture was then cooled to ambienttemperature, filtered through diatomaceous earth, while washing withadditional acetone, and then concentrated under reduced pressure. Thecrude material was then dissolved in a minimal amount of dichloromethaneand purified via silica gel chromatography eluting with a gradient of80-100% ethyl acetate in heptane to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.88 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.24(s, 1H), 4.77 (s, 2H), 1.26 (s, 12H). MS (ESI+) m/z 252.2 (M+H)⁺.

Example 268B 2-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]acetamide

The title compound was prepared according to the procedure outlined inExample 267B substituting Example 268A for Example 267A and heating atabout 120° C. for about 10 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.32 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.48 (s, 1H),7.45 (d, J=8.6 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J=8.7 Hz, 1H), 5.28 (s,2H), 4.78 (s, 2H). MS (ESI+) m/z 257.2 (M+H)⁺.

Example 269 Methyl3-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanoate Example 269AMethyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate

The title compound was prepared according to the procedure outlined inExample 267A substituting methyl acrylate for acrylonitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.91 (s, 1H), 7.57 (s, 1H), 4.35 (t, J=6.73 Hz, 2H),2.87 (t, J=6.75 Hz, 2H), 3.59 (s, 3H), 1.24 (s, 12H). MS (ESI+) m/z281.2 (M+H)⁺.

Example 269B Methyl3-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanoate

The title compound was prepared according to the procedure outlined inExample 267B substituting Example 269A for Example 267A and heating atabout 120° C. for about 20 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.32 (s, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.42 (d, J=8.50Hz, 1H), 7.21 (d, J=8.61 Hz, 1H), 5.28 (s, 2H), 4.37 (t, J=6.71 Hz, 2H),3.61 (s, 3H), 2.92 (t, J=6.69 Hz, 2H). MS (ESI+) m/z 286.2 (M+H)⁺.

Example 270 3-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanamideExample 270A3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanamide

The title compound was prepared according to the procedure outlined inExample 267A substituting acrylamide for acrylonitrile (0.72 g, 53%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.84 (s, 1H), 7.56 (s, 1H), 7.37 (s, 1H),6.88 (s, 1H), 4.30 (t, J=6.80 Hz, 2H), 2.60 (t, J=6.79 Hz, 2H), 1.24 (s,12H). MS (ESI+) m/z 266.2 (M+H)⁺.

Example 270B 3-[4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]propanamide

The title compound was prepared according to the procedure outlined inExample 267B substituting Example 270A for Example 267A and heating atabout 120° C. for about 15 minutes (0.056 g, 22%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.32 (s, 1H), 7.94 (d, J=0.53 Hz, 1H), 7.84 (s, 1H),7.75 (d, J=0.54 Hz, 1H), 7.42 (m, 2H), 7.20 (d, J=8.26 Hz, 1H), 6.89 (s,1H), 5.27 (s, 2H), 4.32 (t, J=6.89 Hz, 2H), 2.65 (t, J=6.89 Hz, 2H). MS(ESI+) m/z 271.0 (M+H)⁺.

Example 271 [4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]acetonitrileExample 271A2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile

The title compound was prepared according to the procedure outlined inExample 268A substituting 2-bromoacetonitrile for 2-bromoacetamide. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.99 (s, 1H), 7.66 (s, 1H), 5.45 (s, 2H),1.25 (s, 12H).

Example 271B tert-butyl3-(bis(tert-butoxycarbonyl)amino)-5-bromo-1H-indazole-1-carboxylate

To 5-bromo-1H-indazol-3-amine (2.00 g, 9.43 mmol) in tetrahydrofuran (20mL) was added 4-(dimethylamino)pyridine (0.230 g, 1.886 mmol) anddi-tert-butyl dicarbonate (6.18 g, 28.3 mmol). The reaction was heatedat 50° C. for about 2 hours, cooled to ambient temperature, andconcentrated under reduced pressure. The residue was dissolved indiethyl ether (100 mL) and then washed sequentially with 1 Nhydrochloric acid (2×25 mL), 1 N sodium hydroxide (2×25 mL) and brine(25 mL). The organic layer was then dried over sodium sulfate, filtered,concentrated under reduced pressure, and dried in a vacuum oven at about60° C. to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) 8.05 (d,J=8.95 Hz, 1H), 7.99 (d, J=1.90 Hz, 1H), 7.81 (dd, J=8.94, 1.89 Hz, 1H),1.65 (s, 9H), 1.40 (s, 18H). MS (ESI+) m/z 512.2 (M+H)⁺.

Example 271C tert-butyl3-(bis(tert-butoxycarbonyl)amino)-5-(1-(cyanomethyl)-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate

A vial was charged with Example 271A (0.682 g, 2.93 mmol), Example 271B(1.25 g, 2.44 mmol), cesium carbonate (1.99 g, 6.10 mmol), 1,4-dioxane(12.5 mL) and water (2.50 mL). After a vacuum/nitrogen purge through asepta, tris(dibenzylideneacetone)dipalladium(0) (0.112 g, 0.122 mmol)and tri-t-butylphosphonium tetrafluoroborate (0.085 g, 0.29 mmol) wereadded and a cap was put on the vial after flushing with nitrogen. Afterabout 6 hours at ambient temperature, the reaction was partitionedbetween saturated aqueous sodium bicarbonate and dichloromethane (50 mLeach). The layers were separated and the aqueous layer was extractedwith additional dichloromethane (2×50 mL). The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude oil was dissolved in aminimal amount of dichloromethane and purified via silica gelchromatography eluting with a gradient of 20-60% ethyl acetate inheptane to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.43 (s, 1H), 8.19 (s, 1H), 8.08 (d, J=9.22 Hz, 1H), 7.93 (m, 2H), 5.53(s, 2H), 1.67 (s, 9H), 1.39 (s, 18H). MS (ESI+) m/z 539.3 (M+H)⁺.

Example 271D [4-(3-amino-1H-indazol-5-yl)-1H-pyrazol-1-yl]acetonitrile

To a solution of tert-butyl3-(bis(tert-butoxycarbonyl)amino)-5-(1-(cyanomethyl)-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate(0.30 g, 0.557 mmol) in dichloromethane (4.0 mL) was addedtrifluoroacetic acid (2.0 mL). After about 45 minutes, the reaction wasslowly quenched with saturated aqueous sodium bicarbonate. The resultingmixture was extracted with dichloromethane (3×25 mL). The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure to give a crude solid.A white precipitate that was suspended in both the initial aqueous layerand the brine layer was filtered and added to the crude solid. Theresulting solid was triturated with dichloromethane/methanol (19:1). Theremaining solid was collected by vacuum filtration and dried in a vacuumoven at about 70° C. to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.37 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H)7.49-7.41 (m, 1H), 7.24 (d, J=8.71 Hz, 1H), 5.52 (s, 2H), 5.31 (s, 2H).MS (ESI+) m/z 239.1 (M+H)⁺.

Example 2724-(3-amino-1H-indazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

3-Cyano-4-fluorophenylboronic acid (0.083 g, 0.503 mmol),4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (0.167 g, 0.554 mmol),sodium carbonate (0.128 g, 1.208 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.030 mmol) werecombined in dimethoxyethane (4 mL) and water (1.5 mL). The reactionmixture was heated in a microwave (CEM-Discover) at about 150° C. forabout 25 minutes. The organic layer was separated and the solvent wasremoved under reduced pressure. To the residue was added ethanol (0.7mL) and hydrazine monohydrate (1 mL). The reaction mixture was heated atabout 80° C. for about 20 hours. The reaction mixture was partitionedbetween water (5 mL) and dichloromethane (100 mL). The organic layer wasseparated and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC using acetonitrile/water (0.05 M ammoniumacetate) gradient elution method to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.42 (s, 1H), 8.25 (s, 1H), 8.21 (d, J=1.36Hz, 1H), 7.92 (d, J=1.37 Hz, 1H), 7.74 (dd, J=8.66, 1.58 Hz, 1H), 7.23(d, J=8.68 Hz, 1H), 5.35 (s, 2H), 2.87 (s, 6H). MS (ESI+) m/z 307.2(M+H)⁺.

Example 273 5-pyrazin-2-yl-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 2-iodopyrazine for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.61 (s, 1H), 9.18 (d, 1H, J=1.6), 8.66 (dd, 1H, J=1.7,2.4), 8.59 (d, 1H, J=1.0), 8.51 (d, 1H, J=2.5), 8.04 (dd, 1H, J=1.8,8.8), 7.35 (d, 1H, J=9.2), 5.54 (s, 2H). MS (ESI+) m/z 212.2 (M+H)⁺.

Example 274 5-thien-2-yl-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 2-iodothiophene for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.47 (s, 1H), 7.99 (d, 1H, J=1.4), 7.55 (dd, 1H, J=1.8,8.8), 7.43 (dd, 1H, J=1.0, 5.1), 7.35 (dd, 1H, J=1.1, 3.6), 7.26 (d, 1H,J=8.6), 7.10 (dd, 1H, J=3.5, 5.1), 5.42 (d, 2H, J=8.8). MS (ESI+) m/z216.1 (M+H)⁺.

Example 275 5-(2-aminopyrimidin-4-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 5-iodopyrimidin-2-amine for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.40 (s, 1H), 8.53 (s, 2H), 7.91 (dd, 1H, J=0.7, 1.5),7.47 (dd, 1H, J=1.8, 8.6), 7.28 (dd, 1H, J=0.7, 8.7), 6.64 (s, 2H), 5.36(s, 2H). MS (ESI+) m/z 227.2 (M+H)⁺.

Example 276 5-(2-methoxypyridin-3-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 3-iodo-2-methoxypyridine for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.43 (s, 1H), 8.14 (dd, 1H, J=1.9, 5.0), 7.86 (s, 1H),7.71 (dd, 1H, J=2.0, 7.2), 7.42 (dd, 1H, J=1.7, 8.7), 7.26 (d, 1H,J=8.6), 7.09 (dd, 1H, J=5.0, 7.3), 5.38 (s, 2H), 3.89 (s, 3H). MS (ESI+)m/z 241.2 (M+H)⁺.

Example 277 5-imidazo[1,2-a]pyridin-3-yl-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 3-bromoimidazo[1,2-a]pyridine for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.52 (dt, 1H, J=1.2, 7.0), 7.99 (dd, 1H, J=0.7, 1.7),7.68 (s, 1H), 7.65 (dt, 2H, J=1.2, 9.0), 7.46 (dd, 1H, J=1.8, 8.6), 7.39(dd, 1H, J=0.8, 8.6), 7.28 (ddd, 1H, J=1.2, 6.6, 9.2), 6.96 (td, 1H,J=1.3, 6.7), 5.47 (s, 2H). MS (ESI+) m/z 250.2 (M+H)⁺.

Example 278N²,N²-dimethyl-N¹-[5-(1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]glycinamide

Example 65 (257 mg, 0.685 mmol) was dissolved in ethanol (15 mL). Thereaction mixture was hydrogenated in an H-Cube apparatus with palladiumhydroxide (20%) on carbon at about 80° C. and about 60 psi for about 8hours. The solvent was removed under reduced pressure and the residuewas purified by reverse phase HPLC using acetonitrile/water (0.05 Mammonium acetate) gradient elution method to afford the title compound.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.16-8.37 (m, 1H), 7.10-7.46 (bs, 2H),7.00-7.34 (bs, 2H), 6.87-7.24 (bs, 2H), 3.33-3.34 (m, 2H). MS (ESI+) m/z286.2 (M+H)⁺.

Example 279 5-(1H-pyrazol-5-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 5-iodo-1H-pyrazole for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.87-7.94 (m, 3H), 7.60-7.63 (m, 1H), 7.48 (dd, J=8.55,1.62 Hz, 1H), 7.19-7.32 (m, 2H), 5.25-5.28 (m, 2H). MS (ESI+) m/z 200.1(M+H)⁺.

Example 280 5-(4-methyl-1H-imidazol-5-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 5-iodo-4-methyl-1H-imidazole for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.85 (s, 1H), 7.52 (d, 2H, J=6.6), 7.22 (m, 1H), 5.32(bs, 2H). 2.37 (s, 3H). MS (ESI+) m/z 214.1 (M+H)⁺.

Example 281 5-(1H-imidazol-4-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 4-iodo-1H-imidazole for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.07 (s, 1H), 7.66 (s, 1H), 7.63 (d, 1H, J=8.6), 7.37 (s,1H), 7.20 (d, 1H, J=8.8), 5.28 (s, 2H). MS (ESI+) m/z 200.1 (M+H)⁺.

Example 282N²,N²-dimethyl-N¹-{5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}glycinamideExample 282A 5-bromo-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 62D substituting 5-bromo-2-fluorobenzonitrile for Example 62C.¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.55 (s, 1H), 7.92 (d, J=1.87 Hz, 1H),7.30 (dd, J=8.79, 1.89 Hz, 1H), 7.19 (d, J=8.78 Hz, 1H), 5.41 (s, 2H).

Example 282B tert-butyl 3-amino-5-bromo-1H-indazole-1-carboxylate

The title compound was prepared according to the procedure outlined inExample 64A substituting Example 282A for Example 62D. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.12 (d, J=1.93 Hz, 1H), 7.95-7.81 (m, 1H), 7.65 (dd,J=8.85, 1.96 Hz, 1H), 6.39 (d, J=4.44 Hz, 1H), 1.58 (m, 9H).

Example 282C tert-butyl5-bromo-3-(2-(dimethylamino)acetamido)-1H-indazole-1-carboxylate

To a mixture of Example 282B (24.43 g, 78 mmol), potassium carbonate (81g, 587 mmol) and 2-(dimethylamino)acetyl chloride hydrochloride (43.3 g,274 mmol) was added tetrahydrofuran (200 mL). The reaction mixture wasstirred at room temperature for about 2 hours. The reaction mixture wasfiltered and the filtrate was washed with water (50 mL). The organiclayer was separated and the aqueous layer was extracted withdichloromethane (3×100 mL). The combined organic extracts were driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith methanol in dichloromethane (5%) to afford the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.72 (s, 1H), 8.19 (d, 1H, J=1.6), 8.03(d, 1H, J=9.0), 7.76 (dd, 1H, J=2.0, 9.0), 3.22 (s, 2H), 2.32 (s, 6H),1.63 (s, 9H).

Example 282D tert-butyl3-(2-(dimethylamino)acetamido)-5-((trimethylsilyl)ethynyl)-1H-indazole-1-carboxylate

To a mixture of Example 282C (2.56 g, 6.44 mmol),bis(triphenylphosphine)palladium(II) chloride (0.225 g, 0.321 mmol), andcopper(I) iodide (0.073 g, 0.383 mmol) was added triethylamine (20 mL,144 mmol) followed by ethynyltrimethylsilane (0.760 g, 7.73 mmol). Thereaction mixture was heated at about 60° C. for about 3 hours. Thereaction mixture was diluted with dichloromethane (100 mL), washed withwater (20 mL) and brine (20 mL), dried over magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with ethyl acetate in dichloromethane(10%) to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.69(s, 1H), 8.08 (s, 1H), 8.04 (d, 1H, J=9.0), 7.62 (d, 1H, J=8.8), 3.21(s, 2H), 2.30 (s, 6H), 1.61 (s, 9H), 0.23 (s, 9H).

Example 282E 2-(dimethylamino)-N-(5-ethynyl-1H-indazol-3-yl)acetamide

To Example 282D (0.303 g, 0.731 mmol) in methanol (5 mL) was addedaqueous potassium hydroxide (1.46 mL, 1.46 mmol, 1.0 N solution). Thereaction mixture was stirred at room temperature for about 1 hour. Thesolvent was removed under reduced pressure and the residue was dissolvedin ethyl acetate (80 mL). The organic layer was separated and washedwith water (10 mL) and brine (10 mL), dried over magnesium sulfate,filtered and concentrated under reduced pressure to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.89 (s, 1H), 10.14 (s, 1H),8.00 (d, 1H, J=12.1), 7.44 (s, 2H), 7.38 (d, 1H, J=8.6), 4.02 (s, 1H),3.17 (s, 2H), 2.33 (s, 6H).

Example 282FN²,N²-dimethyl-N¹-{5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}glycinamide

To a suspension of Example 282E (0.16 g, 0.660 mmol) in tert-butanol(1.2 mL) was added 1-(azidomethyl)-3-methylbenzene (0.098 g, 0.667mmol), then water (1.2 mL). A solution of sodium(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate(0.057 mL, 0.066 mmol, 1.6 M in water) and an aqueous solution of copper(II) sulfate pentahydrate (0.019 mL, 6.6 μmol, 0.34M) was added. Thereaction mixture was heated at about 60° C. for about 2 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby reverse phase HPLC using acetonitrile/water (0.05 M ammonium acetate)gradient elution method to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.77 (s, 1H), 10.05 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H),7.82 (d, 1H, J=8.6), 7.50 (d, 1H, J=8.8), 7.28 (t, 1H, J=7.6), 7.16 (m,4H), 5.59 (s, 2H), 3.18 (s, 2H), 2.34 (s, 6H), 2.30 (s, 3H). MS (ESI+)m/z 390.3 (M+H)⁺.

Example 283 5-(1-benzyl-1H-imidazol-4-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 272 substituting 1-benzyl-4-iodo-1H-imidazole for4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.29 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.61 (d, 1H,J=8.6), 7.46 (s, 1H), 7.36 (m, 5H), 7.17 (d, 1H, J=8.8), 5.28 (s, 2H),5.22 (s, 2H). MS (ESI+) m/z 290.2 (M+H)⁺.

Example 284N¹-{5-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}-N²,N²-dimethylglycinamide

The title compound was prepared according to the procedure outlined inExample 282F substituting 1-(azidomethyl)-4-tert-butylbenzene for1-(azidomethyl)-3-methylbenzene. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.88(s, 1H), 10.05 (s, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.81 (d, 1H, J=8.8),7.50 (d, 1H, J=8.8), 7.41 (d, 2H, J=8.2), 7.30 (d, 2H, J=8.2), 3.18 (s,2H), 2.34 (s, 6H), 1.26 (s, 9H). MS (ESI+) m/z 432.2 (M+H)⁺.

Example 285N²,N²-dimethyl-N¹-{5-[1-(2-piperidin-1-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}glycinamide

The title compound was prepared according to the procedure outlined inExample 282F substituting 1-(2-azidoethyl)piperidine for1-(azidomethyl)-3-methylbenzene. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.91(s, 1H), 10.07 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 7.80 (dd, 1H, J=1.2,8.7), 7.52 (d, 1H, J=8.8), 4.49 (t, 2H, J=6.4), 3.19 (s, 2H), 2.76 (t,2H, J=6.4), 2.41 (s, 4H), 2.35 (s, 6H), 1.69 (s, 3H), 1.47 (m, 4H), 1.37(dd, 2H, J=5.2, 10.2). MS (ESI−) m/z 395.3 (M−H)⁻.

Example 286N²N²-dimethyl-N¹-{5-[1-(2-morpholin-4-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}glycinamide

The title compound was prepared according to the procedure outlined inExample 282F substituting 4-(2-azidoethyl)morpholine for1-(azidomethyl)-3-methylbenzene. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.83(s, 1H), 10.07 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 7.81 (dd, 1H, J=1.3,8.7), 7.52 (d, 1H, J=8.8), 4.53 (t, 2H, J=6.3), 3.55 (m, 4H), 3.19 (s,2H), 2.80 (t, 2H, J=6.3), 2.45 (m, 4H), 2.35 (s, 6H). MS (ESI−) m/z397.3 (M−H)⁻.

Example 287N¹-(5-{1-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-yl)-N²,N²-dimethylglycinamide

The title compound was prepared according to the procedure outlined inExample 282F substituting 4-(2-azidoethyl)-3,5-dimethylisoxazole for1-(azidomethyl)-3-methylbenzene. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.90(s, 1H), 10.07 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.78 (dd, 1H, J=1.3,8.7), 7.52 (d, 1H, J=8.8), 4.51 (t, 2H, J=6.7), 3.19 (s, 2H), 2.93 (t,2H, J=6.7), 2.35 (s, 6H), 2.08 (d, 6H, J=4.3). MS (ESI−) m/z 407.2(M−H)⁻.

Example 288N¹-(5-{1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-yl)-N²,N²-dimethylglycinamide

The title compound was prepared according to the procedure outlined inExample 282F substituting 4-(2-azidoethyl)-3,5-dimethyl-1H-pyrazole for1-(azidomethyl)-3-methylbenzene. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.85(s, 1H), 10.06 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.78 (d, 1H, J=8.8),7.51 (d, 1H, J=8.8), 4.42 (t, 2H, J=6.9), 3.19 (s, 2H), 2.89 (t, 2H,J=7.0), 2.35 (s, 6H), 1.97 (s, 6H). MS (ESI−) m/z 406.2 (M−H)⁻.

Example 2892-(4-{3-[(N,N-dimethylglycyl)amino]-1H-indazol-5-yl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoicAcid

The title compound was prepared according to the procedure outlined inExample 282F substituting 2-azido-2-methylpropanoic acid for1-(azidomethyl)-3-methylbenzene. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.77(s, 1H), 10.03 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 7.85 (dd, 1H, J=0.9,8.7), 7.49 (d, 1H, J=8.6), 3.21 (s, 2H), 2.36 (s, 6H), 1.77 (s, 6H). MS(ESI−) m/z 370.2 (M−H)⁻.

Example 290 Ethyl(4-{3-[(N,N-dimethylglycyl)amino]-1H-indazol-5-yl}-1H-1,2,3-triazol-1-yl)acetate

The title compound was prepared according to the procedure outlined inExample 282F substituting ethyl 2-azidoacetate for1-(azidomethyl)-3-methylbenzene. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.87(s, 1H), 10.08 (s, 1H), 8.51 (s, 1H), 8.26 (s, 1H), 7.82 (dd, 1H, J=1.4,8.7), 7.53 (d, 1H, J=8.8), 5.44 (s, 2H), 4.21 (q, 2H, J=7.0), 3.19 (s,2H), 2.35 (s, 6H), 1.24 (t, 3H, J=7.1). MS (ESI+) m/z 372.2 (M+H)⁺.

Example 291N²,N²-dimethyl-N¹-(5-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-yl)glycinamide

The title compound was prepared according to the procedure outlined inExample 282F substituting (azidomethyl)trimethylsilane for1-(azidomethyl)-3-methylbenzene. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.04(s, 1H), 10.20 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 7.94 (dd, 1H, J=1.3,8.7), 7.65 (d, 1H, J=8.8), 4.18 (s, 2H), 3.33 (s, 2H), 2.49 (s, 6H),0.25 (m, 9H). MS (ESI+) m/z 372.2 (M+H)⁺.

Example 292 N¹-[5-(3-furyl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand furan-3-ylboronic acid for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 12.70 (s, 1H), 9.98 (s, 1H), 8.08 (s, 1H),7.90 (s, 1H), 7.72 (t, 1H, J=1.6), 7.59 (dd, 1H, J=1.4, 8.7), 7.45 (d,1H, J=8.8), 6.87 (s, 1H), 3.17 (s, 2H), 2.33 (s, 6H). MS (ESI+) m/z285.2 (M+H)⁺.

Example 293N²,N²-dimethyl-N¹-[5-(1H-pyrazol-5-yl)-1H-indazol-3-yl]glycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand 1H-pyrazol-5-ylboronic acid for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.68 (s, 1H), 10.01 (s, 1H), 8.12 (s, 1H),7.80 (d, 1H, J=9.0), 7.69 (s, 1H), 7.46 (d, 1H, J=8.6), 6.60 (d, 1H,J=2.0), 3.17 (d, 2H, J=6.4), 2.34 (s, 6H). MS (ESI+) m/z 285.2 (M+H)⁺.

Example 294N²,N²-dimethyl-N¹-(5-pyrimidin-5-yl-1H-indazol-3-yl)glycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand pyrimidin-5-ylboronic acid for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 12.87 (s, 1H), 10.11 (s, 1H), 9.16 (s, 1H),9.09 (s, 2H), 8.16 (s, 1H), 7.75 (dd, 1H, J=1.5, 8.8), 7.60 (d, 1H,J=8.8), 3.18 (s, 2H), 2.33 (s, 6H). MS (ESI+) m/z 297.2 (M+H)⁺.

Example 295N¹-[5-(2,1,3-benzoxadiazol-5-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand benzo[c][1,2,5]oxadiazol-5-ylboronic acid for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 12.87 (s, 1H), 10.15 (s, 1H), 8.29 (s, 1H),8.21 (s, 1H), 8.16 (d, 1H, J=9.4), 7.99 (dd, 1H, J=1.1, 9.4), 7.85 (m,1H), 7.59 (d, 1H, J=8.8), 3.19 (s, 2H), 2.34 (s, 6H). MS (ESI+) m/z337.2 (M+H)⁺.

Example 296N²,N²-dimethyl-N¹-[5-(1H-pyrazol-4-yl)-1H-indazol-3-yl]glycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 12.62 (s, 1H), 9.94 (s, 1H), 7.95 (s, 2H),7.87 (s, 1H), 7.58 (d, 1H, J=8.8), 7.42 (d, 1H, J=8.8), 3.16 (s, 2H),2.34 (s, 6H). MS (ESI+) m/z 285.2 (M+H)⁺.

Example 297N²,N²-dimethyl-N¹-[5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]glycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleor 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.¹H NMR (600 MHz, DMSO-d₆) δ ppm 12.64 (s, 1H), 9.98 (s, 1H), 8.04 (s,1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.55 (dd, 1H, J=1.6, 8.6), 7.43 (d, 1H,J=8.8), 3.87 (s, 3H), 3.17 (s, 2H), 2.35 (s, 6H). MS (ESI+) m/z 299.2(M+H)⁺.

Example 298N¹-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefor1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 12.63 (s, 1H), 10.02 (s, 1H), 7.63 (s, 1H),7.46 (m, 1H), 7.27 (dd, 1H, J=1.6, 8.6), 3.16 (s, 2H), 2.32 (s, 6H),2.18 (s, 6H). MS (ESI+) m/z 323.2 (M+H)⁺.

Example 299N¹-{5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indazol-3-yl}-N²,N²-dimethylglycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileandN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-aminefor1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 12.72 (s, 1H), 10.03 (s, 1H), 8.62 (s, 2H),7.91 (s, 1H), 7.58 (dd, 1H, J=1.6, 8.6), 7.51 (d, 1H, J=8.5), 3.16 (s,8H), 2.33 (s, 6H). MS (ESI+) m/z 340.2 (M+H)⁺.

Example 300N²,N²-dimethyl-N¹-[5-(2-morpholin-4-ylpyrimidin-5-yl)-1H-indazol-3-yl]glycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholinefor1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 12.74 (s, 1H), 10.03 (s, 1H), 8.67 (s, 2H),7.94 (s, 1H), 7.60 (dd, 1H, J=1.8, 8.8), 7.52 (d, 1H, J=8.5), 3.74 (m,4H), 3.67 (m, 4H), 3.17 (s, 2H), 2.33 (s, 6H). MS (ESI+) m/z 382.2(M+H)⁺.

Example 301N²,N²-dimethyl-N¹-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]-1H-indazol-3-yl}glycinamide

The title compound was prepared according to the procedure outlined inExample 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrileand4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholinefor1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 12.63 (s, 1H), 9.96 (s, 1H), 8.09 (s, 1H),7.85 (s, 1H), 7.77 (s, 1H), 7.54 (dd, 1H, J=1.5, 8.8), 7.43 (d, 1H,J=8.5), 4.24 (t, 2H, J=6.6), 3.54 (m, 4H), 3.16 (s, 2H), 2.73 (t, 2H,J=6.6), 2.41 (s, 4H), 2.34 (s, 6H). MS (ESI+) m/z 398.3 (M+H)⁺.

Example 302N¹-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamideExample 302A1-benzyl-5-cyclopropyl-4-(tributylstannyl)-1H-1,2,3-triazole

The title compound was prepared according to the procedure outlined inExample 142A substituting toluene for hexane and (azidomethyl)benzenefor Example 80A. The crude product was used in the next step withoutpurification.

Example 302B5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

The title compound was prepared according to the procedure outlined inExample 142B substituting Example 302A for Example 142A and2-fluoro-5-iodobenzonitrile for 87A. MS (ESI+) m/z 319.2 (M+H)⁺.

Example 302C5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 62D substituting Example 302B for Example 62C. MS (ESI−) m/z299.2 (M−H)⁻.

Example 302D tert-butyl3-amino-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazole-1-carboxylate

The title compound was prepared according to the procedure outlined inExample 64A substituting Example 302C for Example 62D.

Example 302EN¹-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide

The title compound was prepared according to the procedure outlined inExample 64B substituting Example 302D for Example 64A anddimethylaminoacetylchloride hydrochloride for methoxy acetyl chloride.¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.76 (s, 1H), 10.06 (s, 1H), 8.18 (s,1H), 7.79 (d, 1H, J=8.8), 7.50 (d, 1H, J=8.8), 7.34 (m, 5H), 5.68 (s,2H), 3.16 (s, 2H), 2.32 (s, 6H), 1.76 (m, 1H), 1.05 (q, 2H, J=6.1), 0.39(q, 2H, J=5.4). MS (ESI+) m/z 416.3 (M+H)⁺. MS (ESI+) m/z 416.3 (M+H)⁺.

Example 303N¹-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamideExample 303A 3-amino-5-(1-benzyl-1H-pyrazol-4-yl)-indazole-1-carboxylicAcid tert-butyl Ester

The title compound was prepared according to the procedure outlined inExample 64A substituting Example 233B for Example 62D (0.925 g, 100%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.19 (s, 1H), 8.04 (s, 1H), 7.90-7.95(m, 1H), 7.87 (s, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.28-7.36 (m, 5H), 6.27(s, 2H), 5.37 (s, 2H), 1.58 (s, 9H). MS (ESI+) m/z 390 (M+H)⁺.

Example 303BN¹-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]-N²,N²-dimethylglycinamide

A suspension of 2-(dimethylamino)acetic acid (32 mg, 0.308 mmol) andoxalyl chloride (0.31 mL, 0.61 mmol) in dichloromethane (5 mL) anddimethylformamide (2 drops) was stirred at ambient temperature for about1 hour then concentrated under reduced pressure. The residue wassuspended in tetrahydrofuran (3 mL) and added to a suspension of Example303A (40 mg, 0.103 mmol) and potassium carbonate (43 mg, 0.308 mmol) intetrahydrofuran (5 mL). The reaction mixture was stirred at ambienttemperature for about 30 minutes then trifluoroacetic acid (4 mL) wasadded and the reaction mixture was heated at about 60° C. for about 20hours. The reaction mixture was cooled to ambient temperature andconcentrated under reduced pressure, diluted with dichloromethane (20mL) and washed with 15% aqueous sodium hydroxide solution (20 mL). Theorganic extract was separated, dried over magnesium sulfate, filteredand concentrated under reduced pressure. The crude material was purifiedby reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate)gradient elution method to afford the title compound as the acetatesalt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.97 (s, 1H), 8.21 (s, 1H), 7.83(s, 1H), 7.82 (s, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H),7.32-7.40 (m, 2H), 7.25-7.32 (m, 3H), 5.35 (s, 2H), 3.16 (s, 2H), 2.33(s, 6H), 1.91 (s, 3H). MS (ESI+) m/z 375 (M+H)⁺.

Example 304N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-methylglycinamide

The title compound was prepared according to the procedure outlined inExample 303B substituting 2-(tert-butoxycarbonyl(methyl)amino)aceticacid for 2-(dimethylamino)acetic acid and Example 64A for Example 303A.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (s, 1H), 8.28 (s, 1H), 7.78-7.88(m, 1H), 7.45-7.56 (m, 1H), 7.28-7.45 (5H, m), 5.64 (2H, s), 2.37 (s,2H), 1.89 (s, 3H). MS (ESI+) m/z 362 (M+H)⁺.

Example 305N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-pyrrolidin-1-ylacetamideExample 305A tert-butyl5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-(2-bromoacetamido)-1H-indazole-1-carboxylate

To a suspension of Example 64A (500 mg, 1.28 mmol) in tetrahydrofuran(12 mL) was added diisopropylethylamine (0.22 mL, 1.28 mmol). Thereaction mixture was stirred at ambient temperature for about 15 minutesthen 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reactionmixture was stirred at ambient temperature for about 16 hours thenadditional 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. Thereaction mixture was stirred for an additional 15 minutes thenconcentrated under reduced pressure to provide the title compound as abrown solid. This material was used without further purification.

Example 305BN-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-pyrrolidin-1-ylacetamide

To a solution of Example 305A (44 mg, 0.086 mmol) anddiisopropylethylamine (0.015 mL, 0.086 mmol) in acetonitrile (1 mL) wasadded pyrrolidine (0.021 mL, 0.25 mmol) and the reaction mixture washeated at about 60° C. for about 15 minutes. The reaction mixture wascooled to ambient temperature and trifluoroacetic acid (1 mL) was added.The reaction mixture was heated at about 60° C. for about 48 hours. Thereaction mixture was concentrated under reduced pressure, diluted withdichloromethane (20 mL) and washed with 15% aqueous sodium hydroxidesolution (20 mL). The organic layer was separated, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The crudematerial was purified by reverse-phase HPLC using acetonitrile/water(0.05 M ammonium acetate) gradient elution method to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (s, 1H), 8.24 (s, 1H),7.81 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.27-7.45 (m, 5H), 5.64(s, 2H), 3.35 (s, 2H), 2.65 (s, 4H), 1.76 (s, 4H). MS (ESI+) m/z 402(M+H)⁺.

Example 306N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-cyclopentylglycinamide

The title compound was prepared according to the procedure outlined inExample 305B substituting cyclopentanamine for pyrrolidine (0.004 g,12%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (s, 1H), 8.31 (s, 1H),7.73-7.86 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.29-7.45 (m, 5H),5.64 (s, 2H), 3.37 (s, 2H), 2.99-3.14 (m, 1H), 1.60-1.80 (m, 4H),1.30-1.50 (m, 4H). MS (ESI+) m/z 416 (M+H)⁺.

Example 307N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-cyclopropylglycinamide

To a solution of Example 305A (100 mg, 0.196 mmol) anddiisopropylethylamine (0.034 mL, 0.19 mmol) in acetonitrile (1 mL) wasadded cyclopropanamine (11 mg, 0.19 mmol) and the reaction mixture washeated at about 60° C. for about 1 hour. The reaction mixture was cooledto ambient temperature and hydrochloric acid (4 N in dioxane, 1 mL) wasadded. The reaction mixture was stirred at ambient temperature for about16 hours. The reaction mixture was concentrated under reduced pressureand the crude material was purified by reverse-phase HPLC usingacetonitrile/water (0.05 M ammonium acetate) gradient elution method toafford the title compound as the acetate salt. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.18 (s, 1H), 8.28 (s, 1H), 8.56 (s, 1H), 7.81 (d, J=8.6 Hz, 1H),7.49 (d, J=8.7 Hz, 1H), 7.30-7.45 (m, 5H), 5.64 (s, 2H), 3.45 (s, 2H),2.18-2.26 (m, 1H), 1.89 (s, 3H), 0.37-0.45 (m, 2H), 0.29-0.37 (m, 2H).MS (ESI+) m/z 388 (M+H)⁺.

Example 308N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-tetrahydro-2H-pyran-4-ylglycinamide

The title compound was prepared as the acetate salt according to theprocedure outlined in Example 307 substitutingtetrahydro-2H-pyran-4-amine for cyclopropanamine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.56 (s, 1H), 8.31 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.50(d, J=8.7 Hz, 1H), 7.31-7.45 (m, 5H), 5.64 (s, 2H), 3.84 (d, J=11.2 Hz,2H), 3.43 (s, 2H), 3.30 (t, J=10.8 Hz, 2H), 2.62-2.74 (m, 1H), 1.88 (s,3H), 1.75-1.85 (m, 2H), 1.24-1.39 (m, 2H). MS (ESI+) m/z 432 (M+H)⁺.

Example 309N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-(3-hydroxypyrrolidin-1-yl)acetamide

The title compound was prepared as the diacetate salt according to theprocedure outlined in Example 307 substituting pyrrolidin-3-ol forcyclopropanamine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.09 (s, 1H), 8.22(s, 1H), 8.58 (s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H),7.28-7.45 (m, 5H), 5.64 (s, 2H), 4.16-4.26 (m, 1H), 3.34 (s, 2H),2.77-2.93 (m, 2H), 2.52-2.65 (m, 2H), 1.98-2.13 (m, 1H), 1.87 (s, 6H),1.56-1.69 (m, 1H). MS (ESI+) m/z 418 (M+H)⁺.

Example 310N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-(3-hydroxypiperidin-1-yl)acetamide

The title compound was prepared as the acetate salt according to theprocedure outlined in Example 307 substituting piperidin-3-ol forcyclopropanamine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.05 (s, 1H), 8.56(s, 1H), 8.23 (s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H),7.29-7.44 (m, 5H), 5.64 (s, 2H), 3.55-3.67 (m, 1H), 3.20 (s, 2H),2.77-2.88 (m, 1H), 2.60-2.70 (m, 1H), 2.22-2.35 (m, 1H), 2.12-2.23 (m,1H), 1.88 (s, 3H), 1.66-1.78 (m, 2H), 1.43-1.59 (m, 1H), 1.13-1.27 (m,1H). MS (ESI+) m/z 432 (M+H)⁺.

Example 311N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N³,N³-dimethyl-beta-alaninamide

The title compound was prepared as the acetate salt according to theprocedure outlined in Example 307 substituting dimethylamine forcyclopropanamine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.48 (s, 1H), 8.54(s, 1H), 8.26 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H),7.30-7.44 (m, 5H), 5.64 (s, 2H), 2.60 (d, J=6.1 Hz, 2H), 2.54 (d, J=6.3Hz, 2H), 2.21 (s, 6H), 1.90 (s, 3H). MS (ESI+) m/z 390 (M+H)⁺.

Example 312N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-morpholin-4-ylacetamide

The title compound was prepared according to the procedure outlined inExample 307 substituting morpholine for cyclopropanamine. ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.10 (s, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.81 (d,J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.29-7.46 (m, 5H), 5.64 (s, 2H),3.59-3.71 (m, 4H), 3.22-3.28 (m, 2H), 2.54-2.64 (m, 4H). MS (ESI+) m/z418 (M+H)⁺.

Example 313N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide

The title compound was prepared as the diacetate salt according to theprocedure outlined in Example 307 substituting 1-methylpiperazine forcyclopropanamine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.57 (s, 1H), 8.25 (s,1H), 7.81 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.32-7.43 (m, 5H),5.64 (s, 2H), 3.22 (s, 2H), 2.53-2.65 (m, 4H), 2.31-2.45 (m, 4H), 2.17(s, 3H), 1.85 (s, 6H). MS (ESI+) m/z 431 (M+H)⁺.

Example 314N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-(3-oxopiperazin-1-yl)acetamide

The title compound was prepared according to the procedure outlined inExample 307 substituting piperazine-2-one for cyclopropanamine. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.21 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.81(d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.31-7.46 (m, 5H), 5.64 (s,2H), 3.36 (s, 2H), 3.24 (s, 2H), 3.17 (s, 2H), 2.78 (s, 2H). MS (ESI+)m/z 431 (M+H)⁺.

Example 315N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-isopropylglycinamide

The title compound was prepared as the acetate salt according to theprocedure outlined in Example 307 substituting propan-2-amine forcyclopropanamine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (s 1H), 8.31 (s,1H), 7.81 (d, J=8.7 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.31-7.44 (m, 5H),5.64 (s, 2H), 3.39 (s, 2H), 2.73-2.86 (m, 1H), 1.90 (s, 3H), 1.04 (d,J=6.1 Hz, 6H). MS (ESI+) m/z 390 (M+H)⁺.

Example 316N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-cyclohexylglycinamide

The title compound was prepared as the acetate salt according to theprocedure outlined in Example 307 substituting cyclohexanamine forcyclopropanamine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (s, 1H), 8.31 (s,1H), 7.81 (d, J=8.7 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.30-7.44 (m, 5H),5.64 (s, 2H), 3.40 (s, 2H), 1.90 (s, 3H), 1.80-1.88 (m, 2H), 1.63-1.73(m, 2H), 1.50-1.60 (m, 1H), 1.02-1.29 (m, 5H). MS (ESI+) m/z 430 (M+H)⁺.

Example 317N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]acetamide

To a mixture of Example 64A (20 mg, 0.051 mmol) anddiisopropylethylamine (0.063 mL, 0.35 mmol) in tetrahydrofuran (1.5 mL)was added acetyl chloride (0.013 mL, 0.17 mmol) and the reaction mixturewas stirred at ambient temperature for about 1.5 hours. Hydrochloricacid (4 N in dioxane, 1.5 mL) was added and the mixture stirred atambient temperature for about 16 hours. The solvent was removed underreduced pressure and the crude material was purified by reverse-phaseHPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elutionmethod to afford the title compound as the acetate salt. ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.35 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.81 (d,J=8.7 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.33-7.42 (m, 5H), 5.64 (s, 2H),2.13 (s, 3H). MS (ESI−) m/z 331 (M−H)⁻.

Example 318N¹-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N²-cyclobutylglycinamide

The title compound was prepared according to the procedure outlined inExample 307 substituting cyclobutanamine for cyclopropanamine. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.56 (s, 1H), 8.29 (s, 1H), 7.81 (d, J=8.7 Hz,1H), 7.49 (d, J=8.7 Hz, 1H), 7.31-7.45 (m, 5H), 5.64 (s, 2H), 3.31 (s,2H), 2.01-2.20 (m, 2H), 1.48-1.83 (m, 5H). MS (ESI+) m/z 402 (M+H)⁺.

Example 319N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-propylurea

To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) wasadded 1-isocyanatopropane (16 mg, 0.19 mmol) and the reaction mixturewas stirred at ambient temperature for about 3 hours. Additionalisocyanate (0.1 mL) was added and the mixture was heated at about 80° C.for about 16 hours. The reaction mixture was cooled to ambienttemperature and water (5 mL) was added. The resulting precipitate wascollected by filtration then treated with hydrochloric acid (4 Nsolution in dioxane, 3 mL) and stirred at room temperature for about 4.5hours. Diethyl ether (5 mL) was added and the precipitate collected byfiltration. The crude material was purified by reverse-phase HPLC usingacetonitrile/water (0.05 M ammonium acetate) gradient elution method toafford the title compound as the acetate salt. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 9.34 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 7.80 (d, J=8.7 Hz, 1H),7.38 (d, J=8.7 Hz, 1H), 7.31-7.48 (m, 5H), 5.65 (s, 2H), 3.18 (dd,J=6.6, 12.7 Hz, 2H), 1.51 (dd, J=7.1, 14.3 Hz, 2H), 0.91 (t, J=7.3 Hz,3H). MS (ESI+) m/z 376 (M+H)⁺.

Example 320N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]ethanesulfonamide

To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) wasadded ethanesulfonyl chloride (25 mg, 0.19 mmol) and the reactionmixture was stirred at room temperature for about 3 hours. Additionalsulfonyl chloride (25 mg, 0.19 mmol) was added and the reaction mixturewas stirred for about 48 hours. The reaction mixture was concentratedunder reduced pressure and the residue dissolved in dichloromethane (10mL) and washed with 1 N aqueous hydrochloric acid (10 mL). The organicportion was separated, dried under reduced pressure, and treated withhydrochloric acid (4 N in dioxane, 5 mL) and stirred at room temperaturefor about 12 hours. The reaction mixture was concentrated under reducedpressure and the crude material was purified by reverse-phase HPLC usingacetonitrile/water (0.05 M ammonium acetate) gradient elution method toafford the title compound as the acetate salt. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.12 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 7.83 (d, J=8.7 Hz, 1H),7.52 (d, J=8.7 Hz, 1H), 7.29-7.48 (m, 5H), 5.64 (s, 2H), 3.29 (d, J=9.2Hz, 2H), 1.31 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 383 (M+H)⁺.

Example 3215-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(cyclopropylmethyl)-1H-indazol-3-amine

A mixture of Example 64A (100 mg, 0.256 mmol), cyclopropanecarbaldehyde(0.057 mL, 0.76 mmol), sodium triacetoxyborohydride (163 mg, 0.76 mmol)and acetic acid (0.044 mL, 0.76 mmol) in 1,2-dichloroethane (5 mL) wasstirred at ambient temperature for about 2.5 hours. Hydrochloric acid (4N in dioxane, 4 mL) was added and the reaction mixture was stirred forabout 16 hours. The precipitate was collected by filtration, rinsingwith ether (10 mL). The solid was dissolved in dichloromethane (10 mL)and treated with trifluoroacetic acid (0.1 mL) and the reaction mixturewas stirred at room temperature for about 2 hours. The reaction mixturewas neutralized by the addition of 15% aqueous sodium hydroxide solution(about 15 mL) and the organic layer was separated, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The crudematerial was purified by reverse-phase HPLC using acetonitrile/water(0.05 M ammonium acetate) gradient elution method to afford the titlecompound as the acetate salt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.43 (s,1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.32-7.45 (m,5H), 7.26 (d, J=8.6 Hz, 1H), 6.08 (t, J=5.7 Hz, 1H), 5.64 (s, 2H), 3.12(t, J=6.2 Hz, 2H), 1.04-1.22 (m, 1H), 0.35-0.53 (m, 2H), 0.17-0.32 (m,2H). MS (ESI+) m/z 345 (M+H)⁺.

Example 322N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N′-ethylurea

The title compound was prepared according to the procedure outlined inExample 319 substituting isocyanatoethane for 1-isocyanatopropane. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.32 (s, 1H), 8.49 (s, 1H), 8.42 (s, 1H),7.81 (d, J=8.7 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.31-7.49 (m, 5H), 5.65(s, 2H), 3.23 (d, J=6.9 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H). MS (ESI+) m/z362 (M+H)⁺.

Example 3231-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]pyrrolidin-2-one

A suspension of Example 64A (200 mg, 0.51 mmol) anddiisopropylethylamine (0.089 mL, 0.51 mmol) in tetrahydrofuran (5 mL)was stirred for about 15 minutes at ambient temperature then4-bromobutanoyl chloride (0.059 mL, 0.51 mmol) was added. The reactionmixture was stirred for about 16 hours. The precipitate was removed byfiltration and the filtrate concentrated under reduced pressure. Theresidue was taken up in acetonitrile (5 mL) and treated withdiisopropylethylamine (0.089 mL, 0.51 mmol) and heated at about 60° C.for about 16 hours. The reaction mixture was cooled to room temperatureand concentrated under reduced pressure. The residue was treated withhydrochloric acid (4 N in dioxane, 5 mL) and the reaction mixturestirred at room temperature for about 2 hours. The reaction mixture wasconcentrated under reduced pressure and the crude material was purifiedby reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate)gradient elution method to afford the title compound as the acetatesalt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.84 (s, 1H), 8.56 (s, 1H), 8.49(s, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.29-7.46 (m,5H), 5.64 (s, 2H), 3.96 (t, J=6.9 Hz, 2H), 2.56 (t, J=7.9 Hz, 2H),2.25-2.12 (m, 2H). MS (ESI+) m/z 359 (M+H)⁺.

Example 324N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-4-(dimethylamino)butanamide

The title compound was prepared as the diacetate salt according to theprocedure outlined in Example 303B substituting4-(dimethylamino)butanoic acid for 2-(dimethylamino)acetic acid andsubstituting Example 64A for Example 303A. ¹H NMR (400 MHz, DMSO-d₆) δppm 10.34 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.78 (d, J=8.7 Hz, 1H),7.47 (d, J=8.7 Hz, 1H), 7.30-7.41 (m, 5H), 5.62 (s, 2H), 2.41 (t, J=7.2Hz, 2H), 2.28 (t, J=6.8 Hz, 2H), 2.14 (s, 6H), 1.84 (s, 6H), 1.74-1.77(m, 2H). MS (ESI−) m/z 462 (M−H)⁻.

Example 325N-3,4-dihydro-1H-isochromen-4-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 3,4-dihydro-1H-isochromen-4-amine forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.02 (d,1H), 8.4 (m, 1H), 8.22 (m, 1H), 7.75 (m, 2H), 7.2-7.4 (m, 5H), 5.24 (m,1H), 4.75 (m, 2H), 4.02 (m, 1H), 3.8 (m, 1H). MS m/z (ESI+) 361 (M+H)⁺.

Example 326N-(cyclohexylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (35 mg, 0.15 mmol,Example 71A), was dissolved in N,N-dimethylformamide (0.8 mL) followedby the addition of HATU (60 mg, 0.15 mmol) dissolved inN,N-dimethylformamide (0.8 mL). Then a solution of1-cyclohexylmethanamine (17 mg, 0.17 mmol), dissolved inN,N-dimethylformamide (0.8 mL) was added, followed bydiisopropylethylamine (56 μL, 0.31 mmol) dissolved inN,N-dimethylformamide (0.8 mL). The resulting mixture was shaken for 3hours at 40° C. The reaction was filtered, checked by LC/MS andconcentrated to dryness. The residues were dissolved in 1:1 dimethylsulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100%acetonitrile/0.1% trifluoroacetic acid in water) to provide the titleproduct. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 0.91-0.97 (m, 2H),1.12-1.27 (m, 4H), 1.61-1.75 (m, 5H), 3.08-3.16 (m, 2H), 7.22-7.24 (m,1H), 7.71-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.23-8.27 (m, 1H), 8.38-8.41(m, 1H). MS (ESI+) m/z 325 (M+H)⁺; (ESI−) m/z 323 (M−H)⁻.

Example 327N-(3-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-(3-chlorophenyl)methanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.47-4.52(m, 2H), 7.27-7.29 (m, 1H), 7.30-7.42 (m, 4H), 7.72-7.75 (m, 1H),7.89-7.93 (m, 1H), 8.25-8.28 (m, 1H), 8.41-8.42 (m, 1H). MS (ESI+) m/z353 (M+H)⁺; (ESI−) m/z 351 (M−H)⁻.

Example 3285-(1H-indazol-5-yl)-N-(2-methoxybenzyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-(2-methoxyphenyl)methanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 3.82-3.86(m, 3H), 4.45-4.50 (m, 2H), 6.92-6.97 (m, 1H), 7.01-7.04 (m, 1H),7.19-7.24 (m, 1H), 7.26-7.31 (m, 2H), 7.69-7.77 (m, 1H), 7.88-7.93 (m,1H), 8.24-8.28 (m, 1H), 8.38-8.44 (m, 1H). MS (ESI+) m/z 349 (M+H)⁺;(ESI−) m/z 347 (M−H)⁻.

Example 3295-(1H-indazol-5-yl)-N-[2-(trifluoromethyl)benzyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-[2-(trifluoromethyl)phenyl]methanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.66-4.73(m, 2H), 7.29-7.33 (m, 1H), 7.49-7.60 (m, 2H), 7.67-7.79 (m, 3H),7.91-7.94 (m, 1H), 8.26-8.28 (m, 1H), 8.41-8.45 (m, 1H). MS (ESI+) m/z387 (M+H)⁺; (ESI−) m/z 385 (M−H)⁻.

Example 3305-(1H-indazol-5-yl)-N-[3-(trifluoromethyl)benzyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-[3-(trifluoromethyl)phenyl]methanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.57-4.61(m, 2H), 7.28-7.31 (m, 1H), 7.59-7.77 (m, 5H), 7.90-7.94 (m, 1H),8.27-8.28 (m, 1H), 8.40-8.43 (m, 1H). MS (ESI−) m/z 385 (M−H)⁻.

Example 3315-(1H-indazol-5-yl)-N-[4-(trifluoromethyl)benzyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-[4-(trifluoromethyl)phenyl]methanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.55-4.60(s, 2H), 7.27-7.30 (m, 1H), 7.54-7.59 (m, 2H), 7.70-7.76 (m, 3H),7.88-7.94 (m, 1H), 8.24-8.28 (m, 1H), 8.40-8.44 (m, 1H). MS (ESI+) m/z387 (M+H)⁺; (ESI−) m/z 385 (M−H)⁻.

Example 3325-(1H-indazol-5-yl)-N-(pyridin-2-ylmethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-pyridin-2-ylmethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.74-4.84(s, 2H), 7.30-7.34 (m, 1H), 7.68-7.81 (m, 3H), 7.89-7.97 (m, 1H),8.22-8.33 (m, 2H), 8.40-8.45 (m, 1H), 8.67-8.76 (m, 1H). MS (ESI+) m/z320 (M+H)⁺; (ESI−) m/z 318 (M−H)⁻.

Example 3335-(1H-indazol-5-yl)-N-(pyridin-3-ylmethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-pyridin-3-ylmethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.61-4.68(s, 2H), 7.27-7.31 (m, 1H), 7.70-7.75 (m, 1H), 7.83-7.94 (m, 2H),8.24-8.28 (m, 1H), 8.31-8.37 (m, 1H), 8.40-8.44 (m, 1H), 8.69-8.74 (m,1H), 8.77-8.82 (m, 1H). MS (ESI+) m/z 320 (M+H)⁺; (ESI−) m/z 318 (M−H)⁻.

Example 3345-(1H-indazol-5-yl)-N-(pyridin-4-ylmethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-pyridin-4-ylmethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.73-4.80(s, 2H), 7.30-7.33 (m, 1H), 7.73-7.78 (m, 1H), 7.89-7.97 (m, 3H),8.25-8.30 (m, 1H), 8.40-8.46 (m, 1H), 8.76-8.83 (m, 2H). MS (ESI−) m/z318 (M−H)⁻.

Example 335N-(2-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-(2-chlorophenyl)methanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.54-4.58(s, 2H), 7.27-7.32 (m, 1H), 7.33-7.42 (m, 3H), 7.47-7.49 (m, 1H),7.71-7.77 (m, 1H), 7.88-7.98 (m, 1H), 8.24-8.27 (m, 1H), 8.41-8.44 (m,1H). MS (ESI+) m/z 353 (M+H)⁺; (ESI−) m/z 351 (M−H)⁻.

Example 336N-(4-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-(4-chlorophenyl)methanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.42-4.49(m, 2H), 7.22-7.31 (m, 1H), 7.34-7.49 (m, 4H), 7.70-7.76 (m, 1H),7.84-7.92 (m, 1H), 8.17-8.30 (m, 1H), 8.35-8.47 (m, 1H). MS (ESI−) m/z351 (M−H)⁻.

Example 3375-(1H-indazol-5-yl)-N-(1-phenyl-2-piperidin-1-ylethyl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 1-phenyl-2-piperidin-1-ylethanamine forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.12 (d,1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m,6H), 5.2 (m, 1H), 3.2 (m, 2H), 2.3 (m, 4H), 1.2-1.4 (m, 6H). MS (ESI+)m/z 416 (M+H)⁺.

Example 338N-[2-(1H-imidazol-1-yl)-1-phenylethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 2-(1H-imidazol-1-yl)-1-phenylethanamine forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.5 (d,1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.78 (m, 1H), 7.52 (d, 2H), 7.72 (d,2H), 7.2-7.4 (m, 5H), 6.85 (s, 1H), 5.44 (m, 1H), 4.44 (m, 2H). MS(ESI+) m/z 399 (M+H)⁺.

Example 3395-(1H-indazol-5-yl)-N-(2-morpholin-4-yl-1-phenylethyl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 2-morpholin-4-yl-1-phenylethanamine forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.2 (d,1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m,6H), 5.2 (m, 1H), 3.6 (m, 4H), 3.4 (m, 2H), 2.4 (m, 4H). MS (ESI+) m/z418 (M+H)⁺.

Example 3405-(1H-indazol-5-yl)-N-[2-(4-methylpiperazin-1-yl)-1-phenylethyl]isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 2-(4-methylpiperazin-1-yl)-1-phenylethanaminefor piperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.6 (br s, 1H), 9.14(d, 1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4(m, 6H), 5.2 (m, 1H), 3.2 (m, 2H), 2.4 (m, 4H), 2.2 (m, 4H), 2.1 (m,3H). MS (ESI+) m/z 432 (M+H)⁺.

Example 3415-(1H-indazol-5-yl)-N-(1-phenyl-2-pyrrolidin-1-ylethyl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 1-phenyl-2-pyrrolidin-1-ylethanamine forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.14 (d,1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m,6H), 5.18 (m, 1H), 3.2 (m, 2H), 2.4 (m, 4H), 1.8 (m, 3H). MS (ESI+) m/z402.5 (M+H)⁺.

Example 342 tert-butyl2-({[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}amino)-2-phenylethylcarbamate

The title compound was prepared according to the procedure outlined inExample 81B substituting tert-butyl 2-amino-2-phenylethylcarbamate forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.14 (d,1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m,6H), 7.00 (t, 1H), 5.18 (m, 1H), 3.2 (m, 2H), 1.4 (s, 9H). MS (ESI+) m/z449 (M+H)⁺.

Example 3435-(1H-indazol-5-yl)-N-(1-naphthylmethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1-(1-naphthyl)methanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 4.93-4.99(m, 2H), 7.28-7.32 (m, 1H), 7.48-7.66 (m, 4H), 7.70-7.76 (m, 1H),7.86-7.92 (m, 2H), 7.96-8.00 (m, 1H), 8.18-8.23 (m, 1H), 8.24-8.27 (m,1H), 8.38-8.44 (m, 1H);). MS (ESI−) m/z 367 (M−H)⁻.

Example 344 5-(1H-indazol-5-yl)-N-(2-phenylethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 2-phenylethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 2.84-2.92(t, 2H), 3.47-3.57 (t, 2H), 7.18-7.35 (m, 6H), 7.69-7.77 (m, 1H),7.86-7.91 (m, 1H), 8.22-8.29 (m, 1H), 8.37-8.44 (m, 1H). MS (ESI+) m/z333 (M+H)⁺; (ESI−) m/z 331 (M−H)⁻.

Example 3455-(1H-indazol-5-yl)-N-(2-pyridin-2-ylethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 2-pyridin-2-ylethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 3.22-3.29(t, 2H), 3.71-3.75 (t, 2H), 7.14-7.26 (m, 1H), 7.70-7.75 (m, 1H),7.81-7.94 (m, 3H), 8.23-8.29 (m, 1H), 8.35-8.44 (m, 2H), 8.71-8.83 (m,1H). MS (ESI+) m/z 334 (M+H)⁺; (ESI−) m/z 332 (M−H)⁻.

Example 3465-(1H-indazol-5-yl)-N-(2-pyridin-3-ylethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 2-pyridin-3-ylethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 3.01-3.13(t, 2H), 3.55-3.70 (t, 2H), 7.14-7.26 (m, 1H), 7.70-7.77 (m, 1H),7.84-7.95 (m, 2H), 8.25-8.29 (m, 1H), 8.36-8.45 (m, 2H), 8.69-8.75 (m,1H), 8.77-8.84 (m, 1H). MS (ESI+) m/z 334 (M+H)⁺; (ESI−) m/z 332 (M−H)⁻.

Example 3475-(1H-indazol-5-yl)-N-(2-pyridin-4-ylethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 2-pyridin-4-ylethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 3.12-3.23(t, 2H), 3.67-3.71 (t, 2H), 7.20-7.21 (m, 1H), 7.69-7.76 (m, 1H),7.86-7.91 (m, 3H), 8.25-8.27 (m, 1H), 8.38-8.41 (m, 1H), 8.70-8.77 (m,2H). MS (ESI+) m/z 334 (M+H)⁺; (ESI−) m/z 332 (M−H)⁻.

Example 348N-[2-(2-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 2-(2-chlorophenyl)ethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 2.99-3.05(t, 2H), 3.54-3.61 (t, 2H), 7.21-7.23 (m, 1H), 7.26-7.33 (m, 2H),7.35-7.40 (m, 1H), 7.41-7.47 (m, 1H), 7.70-7.75 (m, 1H), 7.87-7.93 (m,1H), 8.23-8.31 (m, 1H), 8.37-8.44 (m, 1H). MS (ESI+) m/z 367 (M+H)⁺;(ESI−) m/z 365 (M−H)⁻.

Example 349N-[2-(3-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 2-(3-chlorophenyl)ethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 2.89 (t,2H), 3.54 (t, 2H), 7.19-7.42 (m, 5H), 7.69-7.77 (m, 1H), 7.86-7.94 (m,1H), 8.22-8.29 (m, 1H), 8.38-8.42 (m, 1H). MS (ESI−) m/z 365 (M−H)⁻.

Example 350N-[2-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 2-(4-chlorophenyl)ethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 2.86 (t,2H), 3.50 (t, 2H), 7.17-7.24 (m, 1H), 7.27-7.41 (m, 4H), 7.71-7.76 (m,1H), 7.85-7.91 (m, 1H), 8.21-8.29 (m, 1H), 8.34-8.44 (m, 1H). MS (ESI−)m/z 365 (M−H)⁻.

Example 351 N-benzyl-N-ethyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except N-benzyl-N-ethylamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 1.06-1.19(m, 3H), 3.37-3.49 (m, 2H), 4.69-4.76 (m, 2H), 7.21-7.28 (m, 1H),7.28-7.49 (m, 5H), 7.69-7.78 (m, 1H), 7.83-7.97 (m, 1H), 8.24-8.32 (m,1H), 8.36-8.46 (m, 1H). MS (ESI+) m/z 347 (M+H)⁺; (ESI−) m/z 345 (M−H)⁻.

Example 3525-(1H-indazol-5-yl)-N-methyl-N-(1-naphthylmethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except N-methyl-N-(1-naphthylmethyl)amine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 3.04-3.11(m, 3H), 5.20-5.35 (m, 2H), 7.20-7.31 (m, 1H), 7.33-7.66 (m, 4H),7.66-7.77 (m, 1H), 7.81-8.18 (m, 4H), 8.20-8.28 (m, 1H), 8.31-8.45 (m,1H). MS (ESI+) m/z 383 (M+H)⁺; (ESI−) m/z 381 (M−H)⁻.

Example 3535-(1H-indazol-5-yl)-N-methyl-N-(2-phenylethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except N-methyl-N-(2-phenylethyl)amine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 2.86-2.97(m, 2H), 3.06-3.13 (m, 3H), 3.70-3.74 (m, 2H), 6.64-7.39 (m, 6H),7.69-7.92 (m, 2H), 8.24-8.44 (m, 2H). MS (ESI+) m/z 347 (M+H)⁺; (ESI−)m/z 345 (M−H)⁻.

Example 3545-(1H-indazol-5-yl)-N-methyl-N-(2-pyridin-2-ylethyl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except N-methyl-N-(2-pyridin-2-ylethyl)amine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 3.07-3.22(m, 3H), 3.26-3.39 (m, 2H), 3.92-4.04 (m, 2H), 6.85-7.14 (m, 1H),7.65-8.05 (m, 4H), 8.23-8.56 (m, 3H), 8.65-8.86 (m, 1H). MS (ESI+) m/z348 (M+H)⁺; (ESI−) m/z 346 (M−H)⁻.

Example 3555-(1H-indazol-5-yl)-N-[(1R)-1-phenylethyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except (1R)-1-phenylethanamine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 1.49-1.54(m, 3H), 5.12-5.20 (m, 1H), 7.23-7.29 (m, 2H), 7.33-7.46 (m, 4H),7.71-7.75 (m, 1H), 7.87-7.91 (m, 1H), 8.22-8.28 (m, 1H), 8.37-8.42 (m,1H). MS (ESI+) m/z 333 (M+H)⁺; (ESI−) m/z 331 (M−H)⁻.

Example 3565-(1H-indazol-5-yl)-N-1,2,3,4-tetrahydronaphthalen-1-ylisoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example326 except 1,2,3,4-tetrahydronaphthalen-1-amine was substituted for1-cyclohexylmethanamine. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 1.72-2.09(m, 4H), 2.68-2.85 (m, 2H), 5.19-5.26 (m, 1H), 7.12-7.24 (m, 4H),7.29-7.35 (m, 1H), 7.69-7.77 (m, 1H), 7.86-7.93 (m, 1H), 8.25-8.30 (m,1H), 8.38-8.43 (m, 1H). MS (ESI−) m/z 357 (M−H)⁻.

Example 3575-(1H-indazol-5-yl)-N-[(1S)-1-(1-naphthyl)ethyl]isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (1S)-1-(1-naphthyl)ethanamine for piperidine.¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.4 (d, 1H), 8.4 (s,1H), 8.25 (s, 1H), 8.22 (br s, 1H), 7.95 (d, 1H), 7.85 (m, 2H), 7.65 (m,2H), 7.5 (m, 3H), 7.3 (s, 1H), 5.9 (m, 1H), 1.65 (d, 3H). MS (ESI+) m/z382.9 (M+H)⁺.

Example 3585-(1H-indazol-5-yl)-N-[(1R)-1-(1-naphthyl)ethyl]isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (1R)-1-(1-naphthyl)ethanamine for piperidine.¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.4 (d, 1H), 8.4 (s,1H), 8.25 (s, 1H), 8.22 (br s, 1H), 7.95 (d, 1H), 7.85 (m, 2H), 7.65 (m,2H), 7.5 (m, 3H), 7.3 (s, 1H), 5.9 (m, 1H), 1.65 (d, 3H). MS (ESI+) m/z382.9 (M+H)⁺.

Example 359N-[3-(dimethylamino)-1-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting N³,N³-dimethyl-1-phenylpropane-1,3-diamine forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.4 (d,1H), 8.4 (s, 1H), 8.25 (s, 1H), 7.92 (m, 1H), 7.7 (m, 1H), 7.3-7.5 (m,6H), 5.15 (m, 1H), 3.2 (m, 2H), 7.75 (s, 6H), 2.35 (m, 1H), 2.15 (m,1H). MS (ESI+) m/z 390 (M+H)⁺.

Example 360N-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting 1-(2,3-dihydro-1,4-benzodioxin-5-yl)methanaminefor piperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.24(t, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.7 (d, 1H), 7.24 (s,1H), 6.9 (m, 3H), 4.4 (d, 2H), 4.3 (d, 2H), 4.25 (d, 2H). MS (ESI+) m/z377 (M+H)⁺.

Example 361N-(3,4-dihydro-2H-1,5-benzodioxepin-6-ylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting1-(3,4-dihydro-2H-1,5-benzodioxepin-6-yl)methanamine for piperidine. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.2 (t, 1H), 8.4 (s, 1H),8.25 (s, 1H), 7.92 (d, 1H), 7.7 (d, 1H), 7.24 (s, 1H), 6.9 (m, 3H), 4.42(d, 2H), 4.15 (m, 4H), 2.2 (m, 2H). MS (ESI+) m/z 391 (M+H)⁺.

Example 3625-(1H-indazol-5-yl)-N-[(1-methyl-1H-indol-4-yl)methyl]isoxazole-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 81B substituting (1-methyl-1H-indol-4-yl)methylamine forpiperidine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 9.24 (t,1H), 8.4 (s, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.7 (d, 1H), 7.38 (m, 3H),7.18 (m, 1H), 7.0 (d, 1H), 6.6 (s, 1H), 4.7 (d, 2H), 3.8 (s, 3H). MS(ESI+) m/z 372 (M+H)⁺.

Example 3635-{3-[(3-phenylpyrrolidin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting 3-phenylpyrrolidine for piperidine. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 8.4 (m, 1H), 8.25 (s, 1H), 7.92 (d,1H), 7.8 (d, 1H), 7.24 (m, 6H), 4.4 (m, 1H), 3.4 (m, 2H), 2.4 (m, 2H),2.0 (m, 2H). MS (ESI+) m/z 359 (M+H)⁺.

Example 3645-{3-[(2-phenylpyrrolidin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting 2-phenylpyrrolidine for piperidine. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 8.4 (m, 1H), 8.25 (s, 1H), 7.92 (d,1H), 7.8 (d, 1H), 7.24 (m, 6H), 5.6 (m, 0.3H), 5.2 (m, 0.7H), 4.0 (m,2H), 1.8-2.0 (m, 4H). MS (ESI+) m/z 390 (M+H)⁺.

Example 3655-{3-[(2-phenylpiperidin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole

The title compound was prepared according to the procedure outlined inExample 81B substituting 2-phenylpiperidine for piperidine. ¹H NMR (300MHz, DMSO-d₆) δ ppm 13.4 (br s, 1H), 8.4 (m, 1H), 8.25 (s, 1H), 7.92 (d,1H), 7.8 (d, 1H), 7.24 (m, 6H), 5.6 (m, 0.3H), 5.2 (m, 0.7H), 4.0 (m,2H), 1.8-2.0 (m, 6H). MS (ESI+) m/z 373 (M+H)⁺.

Example 3665-(1H-indazol-5-yl)-N-[(1S)-1-phenylethyl]isoxazole-3-carboxamide

5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (36 mg, 0.16 mmol,Example 71A), was dissolved in N,N-dimethylformamide (1.0 mL) followedby the addition of HATU (60 mg, 0.16 mmol) dissolved inN,N-dimethylformamide (0.5 mL). Then a solution of(S)-1-phenylethanamine(22 mg, 0.18 mmol), dissolved in N,N-dimethylformamide (0.6 mL) wasadded, followed by diisopropylethylamine (56 μL, 0.32 mmol) dissolved inN,N-dimethylformamide (0.2 mL). The resulting mixture was shaken for 3hours at 40° C. The reaction was filtered, checked by LC/MS andconcentrated to dryness. The residues were dissolved in 1:1 dimethylsulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100%acetonitrile/0.1% trifluoroacetic acid in water) to provide the titleproduct. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm 1.50 (d, 3H), 5.06-5.22 (m,1H), 7.23-7.29 (m, 2H), 7.34-7.38 (m, 2H), 7.40-7.45 (m, 2H), 7.70-7.75(m, 1H), 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.41 (m, 1H), 9.28(d, 1H). MS (ESI+) m/z 333 (M+H)⁺; (ESI−) m/z 331 (M−H)⁻.

Example 3675-(1H-indazol-5-yl)-N-[(1R)-1-(4-methylphenyl)ethyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1R)-1-(4-methylphenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.49 (d,3H), 2.25-2.31 (m, 3H), 5.09-5.18 (m, 1H), 7.14-7.18 (m, 2H), 7.23-7.24(m, 1H), 7.28-7.32 (m, 2H), 7.70-7.75 (m, 1H), 7.86-7.92 (m, 1H),8.22-8.29 (m, 1H), 8.37-8.42 (m, 1H), 9.19 (d, 1H). MS (ESI+) m/z 347(M+H)⁺; (ESI−) 345 (M−H)⁻.

Example 3685-(1H-indazol-5-yl)-N-[(1S)-1-(4-methylphenyl)ethyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1S)-1-(4-methylphenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.48 (d,3H), 2.26-2.30 (m, 3H), 5.05-5.23 (m, 1H), 7.15-7.17 (m, 2H), 7.22-7.25(m, 1H), 7.28-7.32 (m, 2H), 7.67-7.79 (m, 1H), 7.86-7.93 (m, 1H),8.22-8.30 (m, 1H), 8.38-8.41 (m, 1H), 9.21 (d, 1H). MS (ESI−) m/z 345(M−H)⁻.

Example 369N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1R,2S)-1-aminoindan-2-ol was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 2.89-2.96(m, 1H), 3.13-3.21 (m, 1H), 4.55-4.61 (m, 1H), 5.40-5.47 (m, 1H),7.21-7.34 (m, 4H), 7.39-7.42 (m, 1H), 7.72-7.77 (m, 1H), 7.91-7.95 (m,1H), 8.25-8.29 (m, 1H), 8.42-8.45 (m, 1H). MS (ESI−) m/z 359 (M−H)⁻.

Example 370N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1R,2R)-1-aminoindan-2-ol was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 2.72-2.83(m, 1H), 3.13-3.30 (m, 1H), 4.44-4.53 (m, 1H), 5.24-5.32 (m, 1H),7.10-7.18 (m, 1H), 7.20-7.27 (m, 3H), 7.30-7.33 (m, 1H), 7.72-7.78 (m,1H), 7.91-7.93 (m, 1H), 8.24-8.29 (m, 1H), 8.41-8.45 (m, 1H), 9.17 (d,1H). MS (ESI−) m/z 359 (M−H)⁻.

Example 371N-[(1R)-1-(4-bromophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1R)-1-(4-bromophenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.50 (d,3H), 5.08-5.18 (m, 1H), 7.21-7.27 (m, 1H), 7.36-7.41 (m, 2H), 7.50-7.59(m, 2H), 7.70-7.76 (m, 1H), 7.86-7.93 (m, 1H), 8.23-8.29 (m, 1H),8.38-8.41 (m, 1H), 9.32 (d, 1H). MS (ESI+) m/z 411 (M+H)⁺.

Example 372N-[(1S)-1-(4-bromophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1S)-1-(4-bromophenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.49 (d,3H), 5.09-5.19 (m, 1H), 7.23-7.25 (m, 1H), 7.37-7.40 (m, 2H), 7.53-7.57(m, 2H), 7.71-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H),8.38-8.41 (m, 1H), 9.32 (d, 1H). MS (ESI) negative ion 409 (M−H)⁻.

Example 373N-[(1R)-1-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1R)-1-(4-chlorophenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.50 (d,3H), 5.10-5.21 (m, 1H), 7.22-7.26 (m, 1H), 7.38-7.47 (m, 4H), 7.70-7.75(m, 1H), 7.87-7.92 (m, 1H), 8.20-8.28 (m, 1H), 8.38-8.41 (m, 1H), 9.33(d, 1H). MS (ESI−) m/z 365 (M−H)⁻.

Example 374N-[(1S)-1-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1S)-1-(4-chlorophenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.49 (d,3H), 5.12-5.19 (m, 1H), 7.23-7.25 (m, 1H), 7.39-7.47 (m, 4H), 7.71-7.74(m, 1H), 7.87-7.91 (m, 1H), 8.25-8.27 (m, 1H), 8.37-8.43 (m, 1H), 9.32(d, 1H). MS (ESI−) m/z 365 (M−H)⁻.

Example 3755-(1H-indazol-5-yl)-N-[(1S)-1-(2-naphthyl)ethyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1S)-1-(2-naphthyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.61 (d,3H), 5.30-5.38 (m, 1H), 7.25-7.26 (m, 1H), 7.48-7.55 (m, 2H), 7.60-7.63(m, 1H), 7.72-7.75 (m, 1H), 7.88-7.95 (m, 5H), 8.25-8.28 (m, 1H),8.39-8.43 (m, 1H), 9.39 (d, 1H). MS (ESI−) m/z 381 (M−H)⁻.

Example 376N-[1-(4-ethoxyphenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except 2-amino-2-(4-ethoxyphenyl)ethanol was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.32 (t,3H), 3.62-3.67 (m, 1H), 3.70-3.73 (m, 1H), 3.96-4.06 (m, 2H), 4.98-5.06(m, 1H), 6.87-6.91 (m, 2H), 7.23-7.36 (m, 3H), 7.70-7.75 (m, 1H),7.88-7.91 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.42 (m, 1H). MS (ESI−) m/z391 (M−H)⁻.

Example 377N-[2-hydroxy-1-(4-isopropylphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except 2-amino-2-(4-isopropylphenyl)ethanol was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.18 (d,6H), 2.81-2.91 (m, 1H), 3.65-3.70 (m, 1H), 3.72-3.74 (m, 1H), 5.01-5.09(m, 1H), 7.20-7.28 (m, 3H), 7.29-7.35 (m, 2H), 7.72-7.80 (m, 1H),7.87-7.95 (m, 1H), 8.24-8.29 (m, 1H), 8.38-8.44 (m, 1H). MS (ESI−) m/z389 (M−H)⁻.

Example 378N-[1-(3,4-dimethylphenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except 2-amino-2-(3,4-dimethylphenyl)ethanol was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 2.30 (d,6H), 3.56-3.63 (m, 1H), 3.65-3.73 (m, 1H), 5.32-5.42 (m, 1H), 7.06-7.08(m, 2H), 7.23-7.28 (m, 2H), 7.69-7.76 (m, 1H), 7.87-7.95 (m, 1H),8.25-8.28 (m, 1H), 8.39-8.43 (m, 1H). MS (ESI−) m/z 375 (M−H)⁻.

Example 379N-[2-hydroxy-1-(2-methoxyphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except 2-amino-2-(2-methoxyphenyl)ethanol was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 3.60-3.66(m, 2H), 3.84-3.88 (m, 3H), 5.37-5.48 (m, 1H), 6.95 (t, 1H), 7.00-7.06(m, 1H), 7.24-7.31 (m, 2H), 7.32-7.36 (m, 1H), 7.71-7.77 (m, 1H),7.85-7.97 (m, 1H), 8.24-8.28 (m, 1H), 8.40-8.45 (m, 1H). MS (ESI+) m/z379 (M+H)⁺; negative ion 377 (M−H)⁻.

Example 380N-[2-hydroxy-1-(4-methylphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except 2-amino-2-(4-methylphenyl)ethanol was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 2.26-2.32(m, 3H), 3.65-3.70 (m, 1H), 3.72-3.75 (m, 1H), 5.01-5.08 (m, 1H),7.10-7.21 (m, 2H), 7.25-7.35 (m, 3H), 7.70-7.77 (m, 1H), 7.86-7.95 (m,1H), 8.26-8.28 (m, 1H), 8.39-8.46 (m, 1H). MS (ESI+) m/z 363 (M+H)⁺;(ESI−) m/z 361 (M−H)⁻.

Example 3815-(1H-indazol-5-yl)-N-[(1R)-1-(2-methoxyphenyl)ethyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1R)-1-(2-methoxyphenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.43 (d,3H), 3.82-3.86 (m, 3H), 5.41-5.50 (m, 1H), 6.95 (t, 1H), 7.00-7.05 (m,1H), 7.23-7.29 (m, 2H), 7.35-7.39 (m, 1H), 7.71-7.76 (m, 1H), 7.88-7.92(m, 1H), 8.25-8.27 (m, 1H), 8.37-8.43 (m, 1H). MS (ESI+) m/z 363 (M+H)⁺;(ESI−) m/z 361 (M−H)⁻.

Example 382N-[(1S)-1-(3,4-difluorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1S)-1-(3,4-difluorophenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.50 (d,3H), 5.09-5.24 (m, 1H), 7.21-7.30 (m, 2H), 7.35-7.44 (m, 1H), 7.44-7.53(m, 1H), 7.68-7.82 (m, 1H), 7.86-7.94 (m, 1H), 8.26-8.27 (m, 1H),8.39-8.42 (m, 1H). MS (ESI−) m/z 367 (M−H)⁻.

Example 3835-(1H-indazol-5-yl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1R)-1-(3-methoxyphenyl)ethanamine was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.50 (d,3H), 3.75-3.77 (m, 3H), 5.01-5.19 (m, 1H), 6.80-6.87 (m, 1H), 6.97-7.02(m, 2H), 7.21-7.32 (m, 2H), 7.70-7.75 (m, 1H), 7.87-7.95 (m, 1H),8.22-8.31 (m, 1H), 8.37-8.43 (m, 1H). MS (ESI−) m/z 361 (M−H)⁻.

Example 3845-(1H-indazol-5-yl)-N-{(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except (1R)-1-[3-(trifluoromethyl)phenyl]ethanamine was substitutedfor (S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 1.54 (d,3H), 5.22-5.29 (m, 1H), 7.23-7.27 (m, 1H), 7.58-7.69 (m, 2H), 7.71-7.75(m, 2H), 7.77-7.83 (m, 1H), 7.87-7.92 (m, 1H), 8.24-8.29 (m, 1H),8.38-8.42 (m, 1H). MS (ESI−) m/z 399 (M−H)⁻.

Example 385N-[1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except 1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanamine wassubstituted for (S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δppm 1.46 (d, 3H), 4.18-4.25 (m, 4H), 5.01-5.10 (m, 1H), 6.80-6.95 (m,3H), 7.22-7.24 (m, 1H), 7.70-7.74 (m, 1H), 7.87-7.91 (m, 1H), 8.26-8.27(m, 1H), 8.39-8.41 (m, 1H). MS (ESI−) m/z 389 (M−H)⁻.

Example 386N-[1-(3,5-dichlorophenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example366 except 2-amino-2-(3,5-dichlorophenyl)ethanol was substituted for(S)-1-phenylethanamine. ¹H NMR (500 MHz, DMSO-d₆/D2O) δ ppm 3.68-3.72(m, 1H), 3.76-3.78 (m, 1H), 5.02-5.10 (m, 1H), 7.26-7.29 (m, 1H),7.47-7.52 (m, 3H), 7.72-7.75 (m, 1H), 7.89-7.93 (m, 1H), 8.25-8.28 (m,1H), 8.39-8.44 (m, 1H). MS (ESI−) m/z 415 (M−H)⁻.

Example 387 tert-butyl5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate

A solution of triphosgene (0.384 mmol, 114 mg, 98%) in dichloromethane(2 mL) was cooled to 0° C. under nitrogen. Then a mixture oftriethylamine (0.426 mL, 3.07 mmol) and Example 64A (150 mg, 0.384 mmol)in dichloromethane (2 mL) was slowly added dropwise. The resultantmixture was stirred at room temperature for 1 hour. Then6-(trifluoromethyl)pyridin-2-amine (62.3 mg, 0.384 mmol) was addedfollowed by stirring overnight at room temperature. The precipitate wasfiltered off and washed with dichloromethane and water. The product wasdried under vacuum to provide the title compound. MS m/z 579.3 (M+H)⁺.

Example 3885-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-2-yl)carbonyl]-1H-indazol-3-amine

1-Methylpiperidine-3-carboxylic acid hydrochloride (495 mg, 2.756 mmol)was combined with a mixture of dimethylformamide (3 mL) and pyridine (3mL) under nitrogen and stirred for 15 minutes. Then carbonyldiimidazole(446 mg) was added portionwise. The resultant solution was stirred atroom temperature for 1 hour. Then Example 62 (200 mg, 0.689 mmol) wasadded followed by stirring at 60° C. for 2 hours and then at roomtemperature overnight. The reaction mixture was poured into ice waterand brine was added. The cold solution was decanted, and the residue wastaken into dichloromethane and washed with water (2×). The organic layerwas dried with magnesium sulfate, and the volatiles were removed underreduced pressure. The decanted solution was extracted with ethyl acetate(3×). The combined organic layers were washed with brine (2×), driedwith magnesium sulfate, and concentrated. The residue was taken into asmall amount of acetone and then dropped into distilled water. Aprecipitate was collected by filtration, washed with water, and dried toprovide the title compound. MS m/z 579.3 (M+H)⁺.

Example 3895-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-[(dimethylamino)acetyl]-1H-indazol-3-amine

2-(Dimethylamino)acetic acid (710 mg, 6.889 mmol) was dissolved indimethylformamide (6 mL) and pyridine (6 mL) under nitrogen at roomtemperature over 15 minutes. Carbonyldiimidazole (1.11 g) was addedportionwise. The resultant mixture was stirred at room temperature for 1hour. Then Example 62 (500 mg, 1.72 mmol) was added, and the mixture wasstirred overnight at room temperature. The volatile material was removedunder reduced pressure, and the remainder was added to ice water. Sodiumchloride was added and thick oil came out of the cool solution. Thesolution was decanted. The residue was washed with water (3×) and thendried. From the decanted solution, a precipitate came out overnight ofthe water/dimethylformamide mixture. This proved to be starting materialwhich was filtered off and discarded. The product residue wascrystallized in dichloromethane, collected by filtration, rinsed with asmall quantity of dichloromethane and ether. The product was dried toprovide the title compound. MS m/z 376.3 (M+H)⁺.

Example 390 tert-butyl3-amino-5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole-1-carboxylate

Example 62 (6.0 g, 20.66 mmol) was suspended in dichloromethane (340 mL)along with a catalytic amount of dimethylaminopyridine. A solution ofdi-tert-butyl dicarbonate (4.74 g, 21.7 mmol) in dichloromethane (160mL) was added over 1 hour. The reaction mixture was stirred forapproximately 40 hours. Silica gel was added, and the mixture wasconcentrated. This silica mixture was added to a silica gel column andthe material was eluted first with dichloromethane and then with 1%methanol/dichloromethane and lastly with 2% methanol/dichloromethane.The fractions containing the desired product were combined andconcentrated to provide the title compound. MS m/z 391.3 (M+H)⁺.

Example 391N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-piperidin-1-ylacetamide

2-(Piperidin-1-yl)acetic acid (293 mg, 2.05 mmol) was combined withdimethylformamide (3 mL) and pyridine (3 mL). The mixture was stirredfor 15 minutes at room temperature, and then carbonyldiimidazole (332mg) was added portionwise. Stirring was continued at room temperaturefor 1 hour, and then Example 64A (200 mg, 0.512 mmol) was added followedby continued stirring for 24 hours. The reaction mixture was warmed to60° C. for 14 hours. A small amount of the title compound was obtained.MS m/z 416.3 (M+H)⁺.

Example 392N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-morpholin-4-ylacetamide

2-Morpholinoacetic acid (297 mg, 2.05 mmol) was combined withdimethylformamide (3 mL) and pyridine (3 mL). The mixture was stirredfor 15 minutes at room temperature, and then carbonyldiimidazole (332mg) was added portionwise. Stirring was continued at room temperaturefor 1 hour, and then Example 64A (200 mg, 0.512 mmol) was added followedby continued stirring for 28 hours. The reaction mixture was warmed to60° C. for 4 hours and then stirring was continued overnight at roomtemperature. The reaction mixture was warmed again to 60° C. for 7hours. A small amount of the title compound was obtained. MS m/z 418.3(M+H)⁺.

Example 393N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-1-methylpiperidine-2-carboxamide

1-Methylpiperidine-3-carboxylic acid hydrochloride (375 mg, 2.05 mmol)was combined with dimethylformamide (3 mL) and pyridine (3 mL). Themixture was stirred for 15 minutes at room temperature, and thencarbonyldiimidazole (332 mg) was added portionwise. Stirring wascontinued at room temperature for 1 hour, and then Example 64A (200 mg,0.512 mmol) was added followed by continued stirring for 28 hours. Thereaction mixture was warmed to 60° C. for 4.25 hours and then stirringwas continued overnight at room temperature. The reaction mixture waswarmed again to 60° C. for 7 hours. A small amount of the title compoundwas obtained. MS m/z 416.3 (M+H)⁺.

Example 3942-(1H-indazol-5-yl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]-1,3-thiazole-5-carboxamideExample 394A(R)-2-bromo-N-(1-(3-methoxyphenyl)ethyl)thiazole-5-carboxamide

To a stirring solution of 2-bromothiazole-5-carboxylic acid (0.3 g,1.442 mmol), diisopropyl ethylamine (0.205 g, 1.586 mmol) and HATU(0.603 g, 1.586 mmol) in dimethylformamide (7.21 mL, 1.442 mmol) wasadded (R)-1-(3-methoxyphenyl)ethanamine (0.218 g, 1.442 mmol) dropwise.After stirring for 12 hours at 50° C., the reaction was poured intowater (50 mL). The precipitated solid was then collected by filtrationwashing successively with water (2×50 mL) and hexanes (2×50 mL). Therecovered product was used without further purification in the nextstep.

Example 394B(R)-2-(1H-indazol-5-yl)-N-(1-(3-methoxyphenyl)ethyl)thiazole-5-carboxamide

A solution of aqueous cesium carbonate (0.391 g, 1.202 mmol) was addedto a reaction flask containing(R)-2-bromo-N-(1-(3-methoxyphenyl)ethyl)thiazole-5-carboxamide (0.41 g,1.202 mmol), tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate(0.496 g, 1.442 mmol) and Pd(dppf)₂ (1 g, 0.122 mmol) in 1,4-dioxane(6.01 mL, 1.202 mmol). The reaction was heated to 95° C. for 8 hoursunder a steady stream of nitrogen.

The reaction was then cooled and filtered directly through a 3 cm pad ofdiatomaceous earth and concentrated. The residue was dissolved indichloromethane (3 mL) and treated with trifluoroacetic acid (0.093 mL,1.202 mmol). After 1 hour, the trifluoroacetic acid was removed in vacuoand the residue was purified using HPLC (Phenomenex® Luna® C8(2) 5 μm100 Å AXIA™ column (30 mm×75 mm), 70 mL/min, 10-95% acetonitrile/0.1%trifluoroacetic acid in water) to supply the title compound. ¹H NMR (300MHz, methanol-d₄) δ ppm 1.57 (d, 3H) 3.79 (s, 3H) 5.12-5.27 (m, 1H)6.78-6.86 (m, 1H) 6.93-7.02 (m, 2H) 7.26 (t, J=7.80 Hz, 1H) 7.65 (d,J=8.81 Hz, 1H) 8.03 (dd, J=8.82, 1.70 Hz, 1H) 8.18 (s, 1H) 8.40 (s, 1H)8.46 (s, 1H) 8.94 (d, J=7.80 Hz, 1H).

Example 395N-[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-3-fluorobenzamide

The title compound was prepared according to the procedure outlined inExample 64B substituting 3-fluorobenzoyl chloride for methoxy acetylchloride. The title compound was eluted from an ion exchange column(SCX, Varian, 10 g) eluting with 2 M ammonia in methanol. ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.89 (s, 1H), 10.89 (s, 1H), 8.60 (s, 1H), 8.16 (s,1H), 7.93 (br d, 1H), 7.86 (m, 2H), 7.54 (m, 3H), 7.35 (m, 5H), 5.62 (s,2H). MS (ESI+) m/z 413.0 (M+H)⁺.

Example 3965-(1-benzyl-1H-1,2,3-triazol-4-yl)-N,N-dimethyl-1H-indazole-3-carboxamideExample 396A 1-benzyl-4-(tributylstannyl)-1H-1,2,3-triazole

Ethynyltributylstannane (1 mL, 3.4 mmol) and benzyl azide (0.65 mL, 5.2mmol) were heated to 130° C. for 24 hours. The mixture was adsorbed ontosilica gel, and purified by silica gel chromatography eluting with 1:4ethyl acetate:hexanes to afford the title compound.

Example 396B N,N-dimethyl-1H-indazole-3-carboxamide

1H-Indazole-3-carboxylic acid (5.0 g, 30.8 mmol) and carbonyldiimidazole (5.0 g, 33.9 mmol) were dissolved in N,N-dimethylformamide(150 mL) and heated to 60° C. After 2 hours, dimethylamine hydrochloride(4.0 g, 33.9) was added, and the reaction was stirred for an additionalhour at 60° C. The reaction was poured into water, and the aqueous phasewas extracted with ethyl acetate (3×150 mL). The combined organic phaseswere washed sequentially with aqueous sodium bicarbonate, 10%hydrochloric acid, water and brine. After drying over magnesium sulfate,filtering and concentrating in vacuo, the title compound was obtained.

Example 396C 5-iodo-N,N-dimethyl-1H-indazole-3-carboxamide

Example 396B (0.8 g, 4.23 mmol), bis(trifluoroacetoxy)iodobenzene (2.0g, 4.65 mmol), and iodine (0.64 g, 2.53 mmol) were stirred in 30 mL 2:1dichloromethane:tetrahydrofuran for 24 hours. The reaction was quenchedwith sodium bisulfite. The resultant precipitate was collected andwashed with water and hexanes to give the title compound.

Example 396D5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N,N-dimethyl-1H-indazole-3-carboxamide

Example 396A (166 mg, 0.37 mmol), Example 396C (116 mg, 0.37 mmol),tri(o-tolyl)phosphine (22 mg, 0.074 mmol),tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.044 mmol), andtriethylamine (0.06 mL, 0.43 mmol) were combined in dimethylformamide (2mL) in a sealed vial under an inert atmosphere. The vial was sealed andheated to 110° C. for 24 hours. The mixture was adsorbed onto silica geland purified by silica gel chromatography eluting with 5/95 2 M ammoniain methanol/dichloromethane. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.50 (brs, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.92 (d, 1H), 7.65 (d, 1H), 7.39 (m,5H), 5.64 (s, 2H), 3.36 (br s, 3H), 3.09 (br s, 3H). MS (ESI+) m/z 347.0(M+H)⁺.

Example 397 Methyl5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole-3-carboxylate

The title compound was prepared according to the procedure outlined inExample 396D substituting methyl 5-bromo-1H-indazole-3-carboxylate forExample 396C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.97 (br s, 1H), 8.73 (s,1H), 8.54 (s, 1H), 7.95 (d, 1H), 7.72 (d, 1H), 7.39 (m, 5H), 5.66 (s,2H), 3.95 (s, 3H).

Example 3985-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-(1-methyl-1H-imidazol-2-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 396D substituting5-bromo-3-(1-methyl-1H-imidazole-2-yl)-1H-indazole (Woods, K., et al.Bioorg. Med. Chem. 2006, 14, 6832-6846) for Example 396C. ¹H NMR (400MHz, DMSO-d₆) δ ppm 13.20 (br s, 1H), 8.86 (s, 1H), 8.66 (s, 1H), 7.90(d, 1H), 7.64 (d, 1H), 7.39 (m, 5H), 7.31 (s, 1H), 7.13 (s, 1H), 5.65(s, 2H), 4.06 (s, 3H). MS (ESI+) m/z 356.0 (M+H)⁺.

Example 3995-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-morpholin-4-yl-1H-indazole

The title compound was prepared according to the procedure outlined inExample 396D substituting 4-(5-bromo-1H-indazole-3-yl)morpholine(Wrzeciono, U., et al. Pharmazie 1986, 41, 472-474) for Example 396C. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.10 (s, 1H), 8.61 (s, 1H), 8.17 (s, 1H),7.83 (d, 1H), 7.36 (m, 6H), 5.64 (s, 2H), 3.81 (m, 4H), 3.32 (m, 4H). MS(ESI+) m/z 361.0 (M+H)⁺.

Example 4005-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-(4-methylpiperazin-1-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 396D substituting5-bromo-3-(4-methylpiperazine-1-yl)-1H-indazole (Wrzeciono, U., et al.Pharmazie 1986, 41, 472-474) for Example 396C. ¹NMR (400 MHz, DMSO-d₆) δppm 12.08 (s, 1H), 8.62 (s, 1H), 8.16 (s, 1H), 7.82 (d, 1H), 7.36 (m,6H), 5.64 (s, 2H), 3.39 (m, 2H), 3.31 (m, 2H), 2.67 (m, 4H), 2.35 (s,3H). MS (ESI+) m/z 374.1 (M+H)⁺.

Example 401 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-thien-2-yl-1H-indazole

The title compound was prepared according to the procedure outlined inExample 396D substituting 5-bromo-3-(thiophen-2-yl)-1H-indazole (Woods,K., et al. Bioorg. Med. Chem. 2006, 14, 6832-6846) for Example 396C. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 13.25 (br s, 1H), 8.75 (s, 1H), 8.47 (s,1H), 7.95 (d, 1H), 7.80 (d, 1H), 7.63 (d, 1H), 7.57 (d, 1H), 7.38 (m,5H), 7.22 (m, 1H), 5.66 (s, 2H). MS (ESI+) m/z 357.9 (M+H)⁺.

Example 4025-(1-benzyl-5-cyclohexyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amineExample 402A 1-benzyl-5-cyclohexyl-4-(tributylstannyl)-1H-1,2,3-triazole

The title compound was prepared according to the procedure outlined inExample 151A substituting cyclohexaneacetylene for 4-fluorophenylacetylene. MS (ESI+) m/z 531.1 (M+H)⁺.

Example 402B5-(1-benzyl-5-cyclohexyl-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

The title compound was prepared according to the procedure outlined inExample 151B substituting Example 402A for Example 151A.

Example 402C5-(1-benzyl-5-cyclohexyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 151C substituting Example 402B for Example 151B. ¹H NMR (500MHz, DMSO-d₆) δ ppm 11.47 (s, 1H), 7.77 (s, 1H), 7.33 (m, 7H), 5.69 (s,2H), 5.42 (s, 2H), 2.87 (m, 1H), 1.55 (m, 3H), 1.39 (m, 3H), 1.16 (m,3H), 1.00 (m, 1H). MS (ESI+) m/z 373.1 (M+H)⁺.

Example 4035-[1-benzyl-5-(cyclohexylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amineExample 403A1-benzyl-5-(cyclohexylmethyl)-4-(tributylstannyl)-1H-1,2,3-triazole

The title compound was prepared according to the procedure outlined inExample 151A substituting 3-cyclohexyl-1-propyne for 4-fluorophenylacetylene. MS (ESI+) m/z 546.3 (M+H)⁺.

Example 403B5-(1-benzyl-5-(cyclohexylmethyl)-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

The title compound was prepared according to the procedure outlined inExample 151B substituting Example 403A for Example 151A.

Example 403C5-[1-benzyl-5-(cyclohexylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 151C substituting Example 403B for Example 151B. ¹H NMR (500MHz, DMSO-d₆) δ ppm 11.43 (s, 1H), 7.99 (s, 1H), 7.54 (d, 1H), 7.33 (m,6H), 5.64 (s, 2H), 5.43 (br s, 2H), 2.80 (d, 2H), 1.40 (m, 5H), 1.18 (m,1H), 0.83 (m, 5H). MS (ESI+) m/z 387.1 (M+H)⁺.

Example 4045-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-(1,3-thiazol-2-yl)-1H-indazole

The title compound was prepared according to the procedure outlined inExample 396D substituting 2-(5-bromo-1H-indazole-3-yl)thiazole (Woods,K., et al. Bioorg. Med. Chem. 2006, 14, 6832-6846) for Example 396C. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 13.62 (s, 1H), 8.85 (s, 1H), 8.74 (s, 1H),8.05 (d, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.70 (d, 1H), 7.36 (m, 5H),5.67 (s, 2H). MS (ESI+) m/z 359.0 (M+H)⁺.

Example 405 5-(1,5-dibenzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amineExample 405A 1,5-dibenzyl-4-(tributylstannyl)-1H-1,2,3-triazole

The title compound was prepared according to the procedure outlined inExample 151A substituting 3-phenyl-1-propyne for 4-fluorophenylacetylene.

Example 405B 5-(1,5-dibenzyl-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

The title compound was prepared according to the procedure outlined inExample 151B substituting Example 405A for Example 151A.

Example 405C 5-(1,5-dibenzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 151C substituting Example 405B for Example 151B. ¹H NMR (500MHz, DMSO-d₆) δ ppm 11.44 (s, 1H), 8.07 (s, 1H), 7.53 (d, 1H), 7.19 (m,9H), 6.95 (d, 2H), 5.62 (s, 2H), 5.39 (s, 2H), 4.34 (s, 2H). MS (ESI+)m/z 381.1 (M+H)⁺.

Example 4065-(1-benzyl-5-thien-2-yl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amineExample 406A1-benzyl-5-(thiophen-2-yl)-4-(tributylstannyl)-1H-1,2,3-triazole

The title compound was prepared according to the procedure outlined inExample 151A substituting 2-ethynylthiophene for 4-fluorophenylacetylene. MS (ESI+) m/z 532.1 (M+H)⁺.

Example 406B5-(1-benzyl-5-(thiophen-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

The title compound was prepared according to the procedure outlined inExample 151B substituting Example 406A for Example 151A. MS (ESI+) m/z361.0. (M+H)⁺.

Example 406C5-(1-benzyl-5-thien-2-yl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 151C substituting Example 406B for Example 151B. ¹H NMR (500MHz, DMSO-d₆) δ ppm 11.45 (s, 1H), 8.08 (s, 1H), 7.80 (d, 1H), 7.25 (m,7H), 7.04 (d, 2H), 5.57 (s, 2H), 5.38 (s, 2H). MS (ESI+) m/z 373.0(M+H)⁺.

Example 4075-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(2-morpholin-4-ylethyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 396D substituting5-bromo-N-(2-morpholinoethyl)-1H-indazol-3-amine (Wrzeciono, U., et al.Pharmazie 1986, 41, 472-474) for Example 396C. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 11.64 (br s, 1H), 8.46 (s, 1H), 8.25 (s, 1H), 7.70 (d, 1H), 7.36(m, 7H), 5.64 (s, 2H), 3.73 (m, 2H), 3.56 (m, 2H), 3.34 (m, 8H). MS(ESI+) m/z 404.1 (M+H)⁺.

Example 4085-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-3-methyl-1H-indazole

The title compound was prepared according to the procedure outlined inExample 396D substituting Example 151A for Example 396A and5-bromo-3-methyl-1H-indazole (Woods, K., et al. Bioorg. Med. Chem. 2006,14, 6832-6846) for Example 396C. ¹H NMR (500 MHz, DMSO-d₆)

ppm 12.68 (br s, 1H), 7.77 (s, 1H), 7.31 (m, 9H), 6.99 (d, 2H), 5.51 (s,2H), 3.38 (s, 3H). MS (ESI+) m/z 384.1 (M+H)⁺.

Example 4095-[1-benzyl-5-(cyclopentylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amineExample 409A1-benzyl-5-(cyclopentylmethyl)-4-(tributylstannyl)-1H-1,2,3-triazole

The title compound was prepared according to the procedure outlined inExample 151A substituting 3-cyclopentyl-1-propyne for 4-fluorophenylacetylene.

Example 409B5-(1-benzyl-5-(cyclopentylmethyl)-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile

The title compound was prepared according to the procedure outlined inExample 151B substituting Example 409A for Example 151A.

Example 409C5-[1-benzyl-5-(cyclopentylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 151C substituting Example 409B for Example 151B. ¹H NMR (500MHz, DMSO-d₆)

ppm 11.44 (s, 1H), 8.00 (s, 1H), 7.54 (d, 1H), 7.32 (m, 6H), 5.65 (s,2H), 5.42 (s, 2H), 2.91 (d, 2H), 1.82 (m, 1H), 1.38 (m, 4H), 1.23 (m,2H), 0.91 (m, 2H). MS (ESI+) m/z 373.1 (M+H)⁺.

Example 4105-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-butyl-1H-indazol-3-amine

Example 62D (80 mg, 0.27 mmol) and butyraldehyde (29 mg, 0.40 mmol) weredissolved in N,N-dimethylformamide (3 mL). Glacial acetic acid was addeduntil pH=6 then the mixture was stirred at room temperature for 3 hours.Sodium triacetoxyborohydride (229 mg, 1.1 mmol) was added and themixture was stirred overnight. The solvent was removed under reducedpressure and the residue was purified by preparative HPLC on a C18column using a gradient of 35% to 95% acetonitrile/water containing 0.1%trifluoroacetic acid to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 11.41 (s, 1H) 8.41 (s, 1H) 8.25 (s, 1H) 7.68 (d, J=8.73,1H) 7.37-7.43 (m, 5H) 7.26 (d, J=8.73, 1H) 5.97 (t, J=5.55, 1H) 5.64 (s,2H) 3.21-3.30 (m, 2H) 1.57-1.64 (m, 2H) 1.37-1.43 (m, 2H) 0.92 (t,J=7.34, 3H).

Example 411N-benzyl-5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 410 substituting benzaldehyde for butyraldehyde. ¹H NMR (300MHz, DMSO-d₆) δ ppm 11.50 (s, 1H) 8.41 (s, 1H) 8.31 (s, 1H) 7.69 (dd,J=8.73, 1.59, 1H) 7.22-7.43 (m, 12H) 5.64 (s, 2H) 4.47 (s, 2H).

Example 4125-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(4-chlorobenzyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 410 substituting 4-chlorobenzaldehyde for butyraldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 11.48 (s, 1H) 8.42 (s, 1H) 8.29 (s, 1H) 7.69(d, J=8.72, 1H) 7.34-7.44 (m, 9H) 7.28 (d, J=8.72, 1H) 6.71 (t, J=6.15,1H) 5.63 (s, 2H) 4.45 (d, J=5.95, 2H).

Example 4135-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(4-methoxybenzyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 410 substituting 4-methoxybenzaldehyde for butyraldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 11.46 (s, 1H) 8.40 (s, 1H) 8.29 (s, 1H) 7.68(d, J=8.73, 1H) 7.36-7.40 (m, 5H) 7.34 (d, J=8.73, 2H) 7.27 (d, J=8.73,1H) 6.87 (d, J=8.73, 2H) 6.50-6.54 (m, 1H) 5.64 (s, 2H) 4.39 (d, J=4.36,2H) 3.72 (s, 3H).

Example 4145-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(3-fluorobenzyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 410 substituting 3-fluorobenzaldehyde for butyraldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 11.51 (s, 1H) 8.43 (s, 1H) 8.30 (s, 1H) 7.70(d, J=9.12, 1H) 7.19-7.41 (m, 9H) 7.03 (t, J=9.12, 1H) 6.72-6.76 (br s,1H) 5.64 (s, 2H) 4.49 (s, 2H).

Example 4154-({[5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]amino}methyl)benzonitrile

The title compound was prepared according to the procedure outlined inExample 410 substituting 4-cyanobenzaldehyde for butyraldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 11.52 (s, 1H) 8.44 (s, 1H) 8.30 (s, 1H) 7.77(d, J=8.33, 2H) 7.69 (d, J=8.73, 1H) 7.58 (d, J=8.33, 2H) 7.37-7.41 (m,5H) 7.28 (d, J=8.73, 1H) 6.83-6.87 (br s, 1H) 5.64 (s, 2H) 4.56 (s, 2H).

Example 4165-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(2,4-difluorobenzyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 410 substituting 2,4-difluorobenzaldehyde for butyraldehyde. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 11.54 (s, 1H) 8.44 (s, 1H) 8.30 (s, 1H)7.69 (d, J=8.65, 1H) 7.24-7.53 (m, 8H) 7.20 (d, J=8.47, 1H) 6.71 (d,J=6.10, 1H) 5.64 (s, 2H) 4.47 (d, J=5.76, 2H).

Example 4175-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(cyclohexylmethyl)-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined inExample 410 substituting cyclohexanecarboxaldehyde for butyraldehyde. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 11.40 (s, 1H) 8.42 (s, 1H) 8.29 (s, 1H)7.67 (d, J=8.65, 1H) 7.37-7.40 (m, 5H) 7.26 (d, J=9.49, 1H) 6.05 (t,J=5.76, 1H) 5.64 (s, 2H) 3.09 (t, J=6.10, 2H) 1.78-1.85 (m, 2H)1.64-1.73 (m, 4H), 1.15-1.24 (m, 3H) 0.92-1.01 (m, 2H).

Example 418 5-(1-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazole

To a solution of Example 1C (30 mg, 0.21 mmol) in dimethyl sulfoxide(0.25 mL) was added iodobenzene (0.024 mL, 0.21 mmol), a solution ofL-proline (5 mg, 0.042 mmol) and sodium carbonate (5 mg, 0.04 mmol) inwater (0.1 mL), sodium azide (16 mg, 0.25 mmol), a solution of sodiumascorbate (8 mg, 0.04 mmol) in water (0.05 mL) and a solution of copper(II) sulfate pentahydrate (6 mg, 0.02 mmol) in water (0.05 mL) and themixture was heated at 65° C. overnight. The mixture was centrifuged, andthe crude solids were washed with methanol. The methanol wash wasremoved with a pipette. It was then dissolved in dimethyl sulfoxide andpassed through a silica gel plug eluting with ethyl acetate. The productcontaining fractions were combined, concentrated in vacuo, and thentreated with water. The mixture was centrifuged, and the solid waswashed with water and methanol. The washes were removed with a pipetteaffording the title compound. ¹H NMR (400 MHz,) δ ppm 13.17 (s, 1H),9.28 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.96 (m, 3H), 7.65 (m, 3H),7.52 (m, 1H). MS (ESI) m/z 262 (M+H).

Biological Data

ROCK-2 Inhibitory Assay

The compounds of formula (I) were tested for their ability to inhibitN-terminal His6-tagged (SEQ ID NO: 6) recombinant human ROCK-2 residues11-552 expressed by baculovirus in Sf21 cells (Upstate). In 384-wellv-bottom polypropylene plates (Axygen), 1 nM (final concentration) in 10μL recombinant N-terminal His6-tagged (SEQ ID NO: 6) recombinant humanROCK-2 residues 11-552 expressed by baculovirus in Sf21 cells (Upstate)was mixed with 2 μM (final concentration) in 10 μL biotinylated peptidesubstrate (biotin-Aha-KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK (SEQ ID NO: 1))(Genemed), and various concentration of inhibitor (2% DMSO final) inreaction buffer (25 mM HEPES, pH 7.5, 0.5 mM DTT, 10 mM MgCl₂, 100 μMNa₃VO₄, 0.075 mg/mL Triton X-100), and the reaction was initiated byaddition of 5 μM unlabelled ATP containing 0.01 uCi [³³P]-ATP (PerkinElmer). The reaction was quenched after 1 hour by the addition of 50 μLstop buffer (50 mM EDTA, 2M NaCl final concentration). 80 μL of thestopped reactions were transferred to 384-well streptavidin-coatedFlashPlates (Perkin Elmer), incubated 10 minutes at room temperature,washed 3 times with 0.05% Tween-20/PBS using an ELX-405 automated platewasher (BioTek), and counted on a TopCount Scintillation Plate Reader(Packard).

ROCK-1 Inhibitory Assay

The compounds of formula (I) were tested for their ability to inhibitN-terminal His6-tagged (SEQ ID NO: 6), recombinant, human ROCK-1 aminoacids 17-535 expressed by baculovirus in Sf21 cells (Upstate). In384-well v-bottom polypropylene plates (Axygen), 2 nM (finalconcentration) in 10 μL recombinant N-terminal His6-tagged (SEQ ID NO:6), recombinant, human ROCK-1 amino acids 17-535 expressed bybaculovirus in Sf21 cells (Upstate) in reaction buffer was mixed with 2μM (final concentration) biotinylated peptide substrate(biotin-Aha-VRRLRRLTAREAA (SEQ ID NO: 2)) (Genemed), and variousconcentration of inhibitor (2% DMSO final) in 10 μL reaction buffer (25mM HEPES, pH 7.5, 0.5 mM DTT, 10 mM MgCl₂, 100 μM Na₃VO₄, 0.075 mg/mLTriton X-100), and the reaction was initiated by addition of 5 μMunlabelled ATP containing 0.01 uCi [³³P]-ATP (Perkin Elmer). Thereaction was quenched after 1 hour by the addition of 50 μL stop buffer(50 mM EDTA, 2M NaCl final concentration). 80 μL of the stoppedreactions were transferred to 384-well streptavidin-coated FlashPlates(Perkin Elmer), incubated 10 minutes at room temperature, washed 3 timeswith 0.05% Tween-20/PBS using an ELX-405 automated plate washer(BioTek), and counted on a TopCount Scintillation Plate Reader(Packard).

GSK Inhibitory Assay

The compounds of formula (I) were tested for their ability to inhibitN-terminal His6-tagged (SEQ ID NO: 6) GSK-3 expressed by baculovirus inSf21 cells (Upstate). In 384-well v-bottom polypropylene plates(Axygen), 10 μL recombinant N-terminal His-tagged GSK3 expressed bybaculovirus in Sf21 cells (Upstate) was mixed with 10 μl biotinylatedpeptide substrate (biotin-ahx-YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (SEQ ID NO:3)), 2 μM final concentration (Genemed), and various concentration ofinhibitor (2% DMSO final) in reaction buffer (20 mM HEPES, pH 7.5, 1 mMDTT, 10 mM MgCl₂ 100 μM Na₃VO₄, 0.075 mg/mL Triton X-100), and thereaction was initiated by addition of 20 μl [³³P]-ATP, 5 μM finalconcentration, 2 mCi/umol (Perkin Elmer). The reaction was quenchedafter 1 hour by the addition of 50 μL stop buffer (50 mM EDTA, 2M NaClfinal concentration). 80 μL of the stopped reactions were transferred to384-well streptavidin-coated FlashPlates (Perkin Elmer), incubated 10minutes at room temperature, washed 3 times with 0.05°/0 Tween-20/PBSusing an ELX-405 automated plate washer (BioTek), and counted on aTopCount Scintillation Plate Reader (Packard).

Human GSK-3β Inhibitory Assay

Compounds were tested for their ability to inhibit human GlycogenSynthase kinase-3 beta (hGSK-3β) to phosphorylatebiotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE (SEQ ID NO: 3). Compounds wereincubated with 0.5 μCi ³³P-ATP, 10 μM ATP, 0.0125U hGSK-3β (Upstate cellsignaling solutions) and 1 μM substrate(biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE (SEQ ID NO: 3)) in 50 mM HEPES, 10mM MgCl₂, 100 μM Na₃VO₄, 1 mM DTT, 0.0075% Triton, 2% DMSO (total volume50 μL) for 30 minutes at room temperature. The incubation was stopped byaddition of an equal volume of 100 mM EDTA, 4 M NaCl₂. 80 μL of thismixture was added to streptavidin-coated Flashplates (PerkinElmer).Following a wash step, ³³P incorporation was quantified on a MicroBetamicroplate liquid scintillation counter (PerkinElmer). IC50s weredetermined by fitting a sigmoidal dose-response curve to the countsobtained at the different concentrations in GraphPad Prism.

Human GSK-3α Inhibitory Assay

Compounds were tested for their ability to inhibit human GlycogenSynthase kinase-3 alpha (hGSK-3α) 0.5 nM final concentration of tophosphorylate biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE (SEQ ID NO: 3).Compounds were incubated with 0.5 Ci ³³P-ATP, 10 M ATP, 0.0125 U hGSK-3(Upstate cell signaling solutions) and 2 μM substrate(biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE) (SEQ ID NO:3) in 50 mM HEPES, 10mM MgCl₂, 100 μM Na₃VO₄, 1 mM DTT, 0.0075% Triton, 2% DMSO (total volume50 μL) for 30 minutes at room temperature. The incubation was stopped byaddition of an equal volume of 100 mM EDTA, 4M NaCl₂. 80 μL of thismixture was added to streptavidin-coated Flashplates (PerkinElmer).Following a wash step, ³³P incorporation was quantified on a MicroBetamicroplate liquid scintillation counter (PerkinElmer). IC50s weredetermined by fitting a sigmoidal dose-response curve to the countsobtained at the different concentrations in GraphPad Prism.

JAK2 Inhibition Assay

Jak2 kinase activity was assayed by a homogenous time-resolvedfluorescence (HTRF) in vitro kinase assay (Mathis, G., HTRF(R)Technology. J Biomol Screen, 1999. 4(6): p. 309-314). Specifically, 10μL C-terminal His6-tagged (SEQ ID NO: 6), recombinant, human JAK2, aminoacids 808-end, expressed by baculovirus in Sf21 cells (Upstate) wasmixed with 10 μL inhibitor (various concentrations, 2% final DMSO) and10 μL of ATP (5 μM final concentration) in reaction buffer (50 mM HEPES,pH 7.5, 10 mM MgCl₂, 2 mM MnCl₂, 0.1% BSA and 1 mM DTT, 40 μL finalvolume). The reaction was initiated by addition of 10 μL of Bio-PDKpeptide (Biotin-Ahx-KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (SEQ ID NO:4), 0.5 μM final concentration) in a black 384-well plate (Packard).After 60 minutes incubation at room temperature, the reaction wasquenched by addition 60 μL stop/revelation buffer to give 30 mM EDTA, 1μg/mL streptavidin-APC (Prozyme), 50 ng/mL anti-phosphotyrosine mAbPT66-K Europium Cryptate, 30 mM HEPES, pH 7.5, 120 mM KF, 0.005%Tween-20, 0.05% BSA). The quenched reaction was allowed to stand at roomtemperature for 1 hour and then read in a time-resolved fluorescencedetector (Envision, Perkin Elmer) at 615 nm and 665 nm simultaneously.The ratio between the signal of 615 nm and 665 nm was used in thecalculation of the IC₅₀.

Cdc7 Inhibition Assay

Cdc7 kinase assays were carried out in 25 mM HEPES, pH 7.5, 1 mM DTT, 10mM MgCl₂, 100 μM Na₃VO₄, and 0.075 mg/ml Triton X-100 using 12 ngbaculovirus-expressed Cdc7/Dbf4 and 2 μM Jerini peptide substrate A-A11(biotin-C₆linker-TPSDSLIYDDGLS) (SEQ ID NO:5). Reactions were initiatedwith λ-[³³P]-ATP (1 μM, 20 mCi/μmol) and quenched after 1 hour with 5volumes of stop buffer (50 mM EDTA, 2 M NaCl). The reactions wereincubated for 30 minutes on streptavidin-coated plates, washed, andquantified using a TopCount scintillation plate reader (Packard). IC₅₀values are determined via non-linear regression fitting of the data.K_(i) values are generated assuming ATP-competitive (equilibrium)inhibition and using the experimentally determined apparent ATP K_(m) ofCdc7 (0.7 μM).

Ki(μM) Ki(μM) Example 11 data point 6 data point 1 0.0523 10 0.0563 320.0127 35 >1.23 60 0.0556 61 0.0077 62 0.012 63 >1.23 64 0.015 65 0.24266 0.058 73 0.0006 0.0004 80 0.127 87 0.000601 89 0.035 102 0.00210.0012 123 0.023 0.017 125 0.035 146 0.229 150 0.43 151 0.0008 0.0022157 0.64 162 0.00225 163 0.0034 167 0.00105 169 >1.23 171 0.030172 >1.23 185 0.0004 189 0.0019 194 0.068 197 1.23 198 0.0009 0.0008 1990.34 200 0.013 201 0.013 204 0.11 205 0.0024 0.0009 207 0.046 216 0.12217 1.0 218 >1.23 220 0.98 222 0.093 224 0.0063 227 0.015 241 0.473242 >1.23 243 >1.23 254 >1.23 255 >1.23 262 0.041 263 0.022 311 >1.23314 0.18 316 0.50 318 >1.23 319 0.068 320 0.41 321 0.57 322 0.034 3230.18 324 >1.23 395 0.0005 0.0010 396 0.681 397 0.0811 398 0.489 399 0.63400 0.23 401 0.00492 402 0.037 403 0.0082 404 0.258 405 0.0011 4060.0005 407 0.22 408 0.000428 409 0.020 410 0.040 411 0.12 412 0.14 4130.052 414 0.038 415 0.065 416 0.037 417 0.35 418 0.192Phospho-MCM2 ELISA

HCT-116 cells (20,000/well; 96-well format) were treated for 6 hourswith increasing concentrations of compounds (0.01-10 μM in half-logincrements). After removing the medium/inhibitor, the cells were frozenfor 5 minutes and treated on ice with 20 μL of lysis buffer (Invitrogen#FNN0011) for 30 minutes. 80 μL of cold 2% BSA (in PBS) were then addedto each well before transferring 80 μL to MCM2 antibody-coated plates(Bethyl # A300-122A, lot A300-122A-1). The plates were incubatedovernight at 4° C., washed, and then incubated with the sandwichantibody (1:100 rabbit anti-human phospho-MCM2 Ser53; Bethyl #A300-756A,lot A300-756A-2) for 2 hours at room temperature. After another seriesof washes the samples are incubated for 1 hour with detection antibody(XSA-grade goat anti-rabbit-HRP, KPL #074-15-061, lot 50884, diluted to2 μg/mL in 2% BSA). Plates were washed, developed using luminescencesubstrate (SuperSignal Pico for ELISA, Pierce #37069, Lot. HB101408),and read on a Molecular Devices M5 luminometer.

Example EC50 (μM) 60 >10 61 8.787 62 >10 64 >10 73 1.972 87 5.952 89 >10102 3.134 123 >10 151 3.757 162 5.744 163 9.432 167 4.307 185 5.473 1895.324 194 >10 198 4.162 204 6.209 205 >10 222 >10 224 >10 227 >10262 >10 263 >10 319 >10 322 >10 395 2.989 401 >10 403 >10 405 3.100 4060.671 408 1.961 409 >10AlamarBlue Cell Viability Assays

HCT-116 cells (3,000/well; 96-well format) were treated for 72 hourswith increasing concentrations of compounds (0.01-30 μM in half-logincrements). The cells were then incubated in fresh media with 10%AlamarBlue reagent (Invitrogen # DAL1100). AlamarBlue reactions wereincubated according to the manufacturer's instructions (approximately 4hours) and then analyzed using an fmax fluorescence microplate reader(Molecular Devices) using excitation/emission wavelengths of 544/595 nm.Data were analyzed using SOFTmax PRO software provided by themanufacturer.

Example EC50 (μM) 1 >30 32 >30 60 0.143 61 3.978 62 4.539 64 0.422 730.760 87 10.970 89 5.484 102 3.192 123 3.863 151 8.639 162 1.450 1630.928 167 18.153 185 22.636 189 19.202 194 4.392 198 2.900 200 13.536204 0.128 205 0.595 216 19.059 222 2.109 224 2.422 227 1.404 262 3.416263 1.035 319 1.565 322 1.529 395 0.315 397 24.827 401 6.720 402 0.037403 0.008 405 6.622 406 1.495 408 >30 409 13.533Methods—β-Catenin Reporter-Gene Assay

Compounds were tested for their ability to modulate β-catenin-modulatedgene transcription in a LEF/TCF (T-cell factor) reporter gene assay.SY-SY5Y human neuroblastoma cells were transiently transfected with 80ng/well TOPFLASH plasmid (Upstate cell signaling solutions) containingtwo sets of three copies of the TCF binding site upstream of theThymidine kinase minimal promoter and firefly Luciferase open readingframe or with 80 ng/well FOPFLASH plasmid (Upstate cell signalingsolutions) containing three copies of a mutated TCF binding siteupstream of the Thymidine kinase minimal promoter and firefly Luciferaseopen reading frame. In addition, all cells were transiently transfectedwith the 20 ng/well pRL-TK plasmid (Promega) containing the herpessimplex virus thymidine kinase promoter to provide low to moderatelevels of Renilla Luciferase expression. Transfection medium wasexchanged for serum-free medium containing the test substance andincubated for 24 hours at 37° C. The incubation was stopped andquantified using the Dual Glo Luciferase Assay (Promega) as indicatedand quantified on a Pherastar reader (BMG).

Firefly Luciferase activity was normalized for Renilla Luciferaseactivity per well. Subsequently, the normalised TOPFLASH response wascompared to the normalised FOPFLASH response, thus giving the LEF/TCFspecific signal. The maximal response is the maximal ratio between thenormalised TOPFLASH and FOPFLASH signals. Sigmoidal dose-response curveswere fitted using Graphpad Prism.

Murine Asthma Model of Acute Asthma

Female Balb/c mice were purchased from Taconic and housed at AbbottBioresearch Center. Animals were utilized at 8-12 weeks of age. Allprotocols were approved by the Institutional Animal Care and UseCommittee (IACUC). Dexamethasone (Dex), and ovalbumin (OVA) werepurchased from Sigma. Endotoxin was removed from ovalbumin usingDetoxiGel (Pierce) according to manufacturer's protocol and the finalmaterial contained less than 0.1 EU/mg protein. Alum Imject waspurchased from Pierce.

Animals were sensitized to OVA on day 0 and 7 with an i.p. injection of8 μg OVA in 2 mg alum. On days 14 and 16, animals received intra-nasalchallenge of 0.3 μg OVA in 50 μl sterile PBS. Animals were dosed i.p.with a representative compound of formula (I), Example 179, (dissolvedwith 0.5% HMPC, 0.02% Tween 80 in water) twice per day at doses of 3,10, and 30 mg/kg/dose beginning the afternoon of day 13. The final doseof compound was administered 30 minutes prior to measurement of airwayhyperresponsiveness (AHR). Dexamethasone was administered orally once aday on days 13-17 at a dose of 3 mg/kg. All endpoints were analyzed onday 17, 24 hours after the second OVA challenge. AHR was assessed usingunconscious restrained whole body plethysmography. Briefly, a surgicalplane of anesthesia was induced with an i.p. injection of ketamine andxylazine. A tracheal canula was surgically inserted between the thirdand fourth tracheal rings. Spontaneous breathing was prevented by anintravenous (i.v.) jugular vein injection of pancuronium bromide.Animals were placed in a whole body plethysmograph (Buxco) andmechanically ventilated with 0.2 mL room air at 150 breaths per minutewith a volume-controlled ventilator (Harvard Apparatus). Pressure in thelung and flow within the plethysmograph were measured using transducers,and lung resistance was calculated as pressure/flow using Biosystem Xasoftware. Baseline resistance as well as resistance following challengewith methacholine (3, 10 or 30 mg/mL) that was delivered with an inlineultrasonic-nebulizer were measured. Upon completion of pulmonaryfunction testing, the lungs were lavaged 4 times with 0.5 mL sterilePBS. Lavage fluid was analyzed for IL-13, AMCase, Muc5ac and cellularinfiltrates. The efficacy of the test compound was tested at doses of 3,10 and 30 mg/kg b.i.d. (6, 20, 60 mg/kg/day). Challenge with OVA causedan increase in lung resistance to 6.90 cm H₂O/mL/sec vs. 4.65 cmH₂O/mL/sec in animals challenged with PBS. Treatment of mice with thetest compound significantly inhibited (p<0.001) methacholine-inducedairways resistance down to 4.55 cm H₂O/mL/sec and 4.77 cm H₂O/mL/sec atdoses ranging between 1 and 100 mg/kg. The preferred compounds require adose of less than 50 mg/kg to exhibit said response. The most preferredcompounds require a dose of less than 30 mg/kg to exhibit said response.This inhibition was equivalent to measurements taken in the PBSchallenged group (4.65 cm H₂O/mL/sec) and to treatment of 3 mg/kgdexamethasone (4.76 cm H₂O/mL/sec).

IL-13 Measurement:

IL-13 concentrations in the bronchioalveolar lavage fluid (BAL) weremeasured by ELISA (R & D Systems) according to manufacturer'sinstructions. IL-13 concentrations in the BAL fluid were significantlyinduced to 102.5 pg/mL in OVA challenged mice as compared to levelsbelow detection in the PBS challenged group. This induction wassignificantly inhibited (p<0.05) by 60% after administration of arepresentative compound of formula (I), Example 179, at the 30 mg/kgdose. There was no significant inhibition at the 3 mg/kg or 10 mg/kgdose groups.

AMCase Measurement:

Acidic mammalian chitinase (AMCase) activity was determined in a 1:10dilution of BAL fluid with 0.01% BSA, 30 mM sodium citrate, 60 mM sodiumphosphate, pH 5.2 in the presence of 80 μM 4-methylumbelliferylβ-D-N,N′-diacetylchitobioside. Reactions were incubated for 15 minutesat room temperature and quenched by addition of 100 μL of 1 Mglycine/NaOH pH 10.6. Product formation was determined by fluorescenceemission at 460 nm using excitation at 385 nm on a Fluoroskan Ascentfluorometer. AMCase activity was induced to 28.5 U in OVA challengedanimals compared to 2.17 U in the PBS challenged animals. This inductionwas significantly inhibited (p<0.01) in the 30 mg/kg group by 45% aftera representative compound of formula (I), Example 179 was administered.

MUC5AC Measurement:

Concentrations of the mucin gene MUC5AC were quantitated by ELISAformat. Briefly, BAL samples are diluted 1:2 in buffer (2% BSA in PBS)and plated onto high protein binding 96-well plates (Costar) and dried.After a series of washes, a 1:100 dilution of biotinylated MUC5ACantibody (Clone 45M, LabVision) was added for 1 hour. Plates are washedand a 1:3000 dilution of streptavidin-HRP (Southern Biotech) was addedto the plate for 15 minutes. Plates were then developed using a TMBsubstrate (Sigma) for 30 minutes. The reaction was stopped using 1MH₂SO₄ and then read in a spectrophotometer at OD 450 nm. Levels ofMUC5AC were reduced by 35% after administration of a representativecompound of formula (I), Example 179 at 35 mg/kg.

Determination of Antinociceptive Effect: Models for Neuropathic Pain

Spinal Nerve (L5/L6) Ligation Model of Neuropathic Pain.

As previously described in detail by Kim and Chung (Kim S. H.; Chung J.M. An experimental model for peripheral neuropathy produced by segmentalspinal nerve ligation in the rat. Pain 1992, 50, 355-363), a 1.5 cmincision was made dorsal to the lumbosacral plexus. In anesthetizedrats, the paraspinal muscles (left side) were separated from the spinousprocesses, the L5 and L6 spinal nerves isolated, and tightly ligatedwith 3-0 silk threads. Following hemostasis, the wound was sutured andcoated with antibiotic ointment. The rats were allowed to recover andthen placed in a cage with soft bedding for 14 days before behavioraltesting for mechanical allodynia.

Sciatic Nerve Ligation Model of Neuronathic Pain.

As previously described in detail by Bennett and Xie (Bennett G. J.; XieY-K. A peripheral mononeuropathy in rat that produces disorders of painsensation like those seen in man. Pain 1988, 33, 87-107), inanesthetized rats, a 1.5 cm incision was made 0.5 cm below the pelvisand the biceps femoris and the gluteous superficialis (right side) wereseparated. The sciatic nerve was exposed, isolated, and four looseligatures (5-0 chromic catgut) with 1 mm spacing were placed around it.The rats were allowed to recover and then placed in a cage with softbedding for 14 days before behavioral testing for mechanical allodyniaas described above. In addition, animals were also tested for coldallodynia by dipping their hind paw in a cold-water bath (4.5° C.) anddetermining the paw withdrawal latency.

Selected analogs of compounds of formula (I), Examples 160 and 179,dosed either i.p. or p.o. demonstrated greater than 30% inhibition oftactile allodynia in the Chung and Bennett models of neuropathic paindescribed herein at doses ranging from 1-150 mg/kg.

In summary, a representative compound of formula (I) in a mouse model ofacute asthma was effective in inhibiting airway resistance in a doserange between 1 and 100 mg/kg. High dose (30 mg/kg) treatment alsoinhibited IL-13 induction as well as AMCase activity and MUC5AC levelsin the BAL fluid.

Representative compounds of formula (I) in rat models of neuropathicpain were effective as demonstrated by a greater than 30% inhibition oftactile allodynia at doses ranging from 1-150 mg/kg.

The compounds of formula (I) were found to inhibit human ROCK-2,N-terminal His-tagged GSK-3β, human GSK-3β, His6-tagged (SEQ ID NO: 6),recombinant, human JAK2 and Firefly Luciferase exhibiting an IC₅₀ ofless than 10 nM to about 10 μM, preferably less than 10 nM to about 1.0μM. More preferably, compounds of formula (I) were found to inhibithuman ROCK-2, N-terminal His-tagged GSK-3β, human GSK-3β, His6-tagged(SEQ ID NO: 6), recombinant, human JAK2 and Firefly Luciferaseexhibiting an IC₅₀ of less than 10 nM to about 100 nM, and mostpreferably less than 10 nM.

In addition, certain compounds of formula (I) exhibited inhibition ofhuman ROCK-2 with a selectivity of greater than 10 fold against a panelof 50 kinase targets. Certain compounds of formula (I) exhibitedinhibition of human GSK-3β with a selectivity of greater than 10 foldagainst a panel of 50 kinase targets. Certain compounds of formula (I)exhibited inhibition of His6-tagged (SEQ ID NO: 6), recombinant, humanJAK2 with a selectivity of greater than 10 fold against a panel of 50kinase targets.

Certain compounds of formula (I) were also found to inhibit Cdc7exhibiting a Ki of about 0.1 nM to about 10 μM. More preferably,compounds of formula (I) were found to inhibit Cdc7 exhibiting a Ki ofabout 0.1 nM to 100 nM, and most preferably less than 10 nM. Compoundsfound to inhibit Cdc7 preferably have an EC₅₀ less than 5 μM in both theAlamarBlue cell viability assay and Phospho-MCM2 ELISA assay and morepreferably less than 1 μM.

Methods of Administration

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, topically (as by powders, ointments ordrops), bucally or as an oral or nasal spray. The term “parenterally,”as used herein, refers to modes of administration that includeintravenous, intramuscular, intraperitoneal, intrasternal, subcutaneousand intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such as propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions, which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable carrier or excipient, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants, which maybe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. The phrase “therapeutically effectiveamount” of the compound of the invention means a sufficient amount ofthe compound to treat disorders, at a reasonable benefit/risk ratioapplicable to any medical treatment. It will be understood, however,that the total daily usage of the compounds and compositions of thepresent invention will be decided by the attending physician within thescope of sound medical judgment. The specific therapeutically effectivedose level for any particular patient will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

The term “pharmaceutically acceptable salt,” as used herein, means saltsderived from inorganic or organic acids. The salts can be prepared insitu during the final isolation and purification of compounds of Formula(I) or separately by reacting the free base of a compound of Formula (I)with an inorganic or organic acid. Representative acid addition saltsinclude, but are not limited to, acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate,fumarate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, sulfate, (L) tartrate, (D) tartrate, (DL)tartrate, thiocyanate, phosphate, glutamate, bicarbonate,p-toluenesulfonate, and undecanoate.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like.Prodrugs of the present invention may be rapidly transformed in vivo tocompounds of Formula (I), for example, by hydrolysis in blood.

The present invention contemplates compounds of Formula (I) formed bysynthetic means or formed by in vivo biotransformation.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others, are equivalent to the unsolvatedforms for the purposes of the invention.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.003 to about 30mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.01 to about 10 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

Methods of Use

Protein kinases can be classified into broad groups based upon theidentity of the amino acid(s) that they target (serine/threonine,tyrosine, lysine, and histidine). For example, tyrosine kinases includereceptor tyrosine kinases (RTKs), such as growth factors andnon-receptor tyrosine kinases, such as the src kinase family. There arealso dual-specific protein kinases that target both tyrosine andserine/threonine, such as cyclin dependent kinases (CDKs) andmitogen-activated protein kinases (MAPKs).

The protein tyrosine kinases (PTKs) compose a large family of kinasesthat regulate cell to cell signals involved in growth, differentiation,adhesion, motility, and death (Pearson, M. et al., In Protein TyrosineKinases; Fabbro, D., McCormick, F., Eds.; Humana Press Inc., 2006; pp1-29.). Members of the tyrosine kinase include, but are not limited to,Yes, BMX, Syk, EphA1, FGFR3, RYK, MUSK, JAK1 and EGFR. Tyrosine kinasesare distinguished into two classes, i.e., the receptor type andnon-receptor type tyrosine kinases. Interestingly, the entire family oftyrosine kinases consists of at least 90 characterized kinases with atleast 58 receptor type and at least 32 nonreceptor type kinasescomprising at least 30 total subfamilies. Tyrosine kinases have beenimplicated in a number of diseases in humans, including diabetes andcancer (Pearson, M. et al., In Protein Tyrosine Kinases; Fabbro, D.,McCormick, F., Eds.; Humana Press Inc., 2006; pp 1-29.). Tyrosinekinases are often involved in most forms of human malignancies and havebeen linked to a wide variety of congenital syndromes (Robertson et al.,Trends Genet. 16:265-271, 2000).

The non-receptor tyrosine kinases represent a group of intracellularenzymes that lack extracellular and transmembrane sequences. Currently,over 32 families of non-receptor tyrosine kinases have been identified(Robinson et al., Oncogene 19, 5548-5557, 2000). Representative examplesinclude Src, Btk, Csk, ZAP70 and Kak families. In particular, the Srcfamily of non-receptor tyrosine kinase family is the largest, consistingof Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk protein tyrosinekinases. The Src family of kinases have been linked to oncogenesis, cellproliferation and tumor progression. Many of the protein tyrosinekinases have been found to be involved in cellular signaling pathwaysinvolved in various pathological conditions including but not limited tocancer and hyperproliferative disorders and immune disorders.

The cyclin dependent kinases CDKs represent a group of intracellularenzymes that control progression through the cell cycle and haveessential roles in cell proliferation (Cohen, P. Nature Reviews DrugDiscovery 1, 309-315, 2002). Representative examples of CDKs include,but are not limited to, cyclin dependent kinase 2 (CDK2), cyclindependent kinase 7 (CDK7), cyclin dependent kinase 6 (CDK6) and celldivision control 2 protein (CDC2). CDKs have been implicated in theregulation of transitions between different phases of the cell cycle,such as the progression from a quiescent stage in G1 (the gap betweenmitosis and the onset of DNA replication for a new round of celldivision) to S (the period of active DNA synthesis), or the progressionfrom G2 to M phase, in which active mitosis and cell division occur(Rowell et al. Critical Reviews in Immunology 26(3), 189-212, 2006). CDKcomplexes are formed through association of a regulatory cyclin subunit(e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinasesubunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). CDKs display anabsolute dependence on the cyclin subunit in order to phosphorylatetheir target substrates, and different kinase/cyclin pairs function toregulate progression through specific portions of the cell cycle.Furthermore, CDKs have been implicated in various disease states,including but not limited to, those displaying the cancer phenotype,various neoplastic disorders and in neurological disorders (Pallas etal. Current Medicinal Chemistry: Central Nervous System Agents 5(2),101-109, 2005).

The mitogen activated protein (MAP) kinases participate in thetransduction of signals to the nucleus of the cell in response toextracellular stimuli. Representative examples of MAP kinases include,but are not limited to, mitogen activated protein kinase 3 (MAPK3),mitogen-activated protein kinase 1 (ERK2), mitogen-activated proteinkinase 7 (MAPK7), mitogen-activated protein kinase 8 (JNK1),mitogen-activated protein kinase 14 (p38 alpha), mitogen-activatedprotein kinase 10 (MAPK 10), JNK3 alpha protein kinase, stress-activatedprotein kinase JNK2 and mitogen-activated protein kinase 14 (MAPK14).MAP kinases are a family of proline-directed serine/threonine kinasesthat mediate signal transduction from extracellular receptors or heathshock, or UV radiation (Barr et al., Trends in Pharmacological Sciences27(10), 525-530, 2006). MAP kinases activate through the phosphorylationof threonine and tyrosine by dual-specificity protein kinases, includingtyrosine kinases such as growth factors. Cell proliferation anddifferentiation have been shown to be under the regulatory control ofmultiple MAP kinase cascades (Sridhar et al., Pharmaceutical Research,17:11 1345-1353, 2000). As such, the MAP kinase pathway plays criticalroles in a number of disease states, for example, defects in activitiesof MAP kinases have been shown to lead to aberrant cell proliferationand carcinogenesis (Qi et al., Journal of Cell Science 118(16),3569-3572, 2005). Moreover, MAP kinase activity has also been implicatedin insulin resistance associated with type-2 diabetes (Fujishiro et al.Recent Research Developments in Physiology 1(Pt. 2), 801-812, 2003).

The p90 ribosomal S6 kinases (Rsk) are serine/threonine kinases whichfunction in mitogen-activated cell growth and proliferation,differentiation, and cell survival. Examples of members of the Rskfamily of kinases include, but are not limited to, ribosomal protein S6kinase, 90 kDa, polypeptide 2 (Rsk3), ribosomal protein S6 kinase, 90kDa, polypeptide 6 (Rsk4), ribosomal protein S6 kinase, 90 kDa,polypeptide 3 (Rsk2) and ribosomal protein S6 kinase, 90 kDa,polypeptide 1 (Rsk1/p90Rsk). The Rsk family members are activated byextracellular signal-related kinases and phosphoinositide-dependentprotein kinase 1 (Frodin and Gammeltoft, Mol. Cell. Endocrinol. 151,65-77, 1999). Under basal conditions, RSK kinases are localized in thecytoplasm of cells and upon stimulation by mitogens, the activated(phosphorylated by extracellular-related kinase) RSK transientlytranslocates to the plasma membrane where they become fully activated.The fully activated RSK phosphorylates substrates that are involved incell growth, proliferation, differentiation, and cell survival (Clark etal. Cancer Research 65, 3108-3116, 2005). RSK signaling pathways havealso been associated with the modulation of the cell cycle (Gross etal., J. Biol. Chem. 276, 46099-46103, 2001). Current data suggests thatsmall molecules that inhibit Rsk may be useful therapeutic agents forthe prevention and treatment of cancer and inflammatory diseases.

Members of the checkpoint protein kinase family (CHK) areserine/threonine kinases that play an important role in cell cycleprogression. Examples of members of the checkpoint family include, butare not limited to, CHK1 and CHK2. Checkpoints kinases are controlsystems that coordinate cell cycle progression by influencing theformation, activation and subsequent inactivation of thecyclin-dependent kinases. Checkpoints kinases prevent cell cycleprogression at inappropriate times, maintain the metabolic balance ofcells while the cell is arrested, and in some instances can induceapoptosis (programmed cell death) when the requirements of thecheckpoint have not been met (Nurse, Cell, 91, 865-867, 1997; Hartwellet al., Science, 266, 1821-1828, 1994). Members of the checkpoint familyof kinases have been implicated in cell proliferative disorders, cancerphenotypes and other diseases related to DNA damage and repair (Kumagaiand Dunphy Cell Cycle, 5, 1265-1268 (2006); Xiao et al., MolecularCancer Therapeutics 5, 1935-1943, 2006).

Aurora kinases are a family of multigene mitotic serine-threoninekinases that functions as a class of novel oncogenes. These kinasescomprise aurora-A and aurora-B members. Aurora kinases arehyperactivated and/or over-expressed in several solid tumors includingbut not limited to, breast, ovary, prostate, pancreas, and colorectalcancers. In particular aurora-A is a centrosome kinase that plays animportant role cell cycle progression and cell proliferation. Aurora-Ais located in the 20q13 chromosome region that is frequently amplifiedin several different types of malignant tumors such as colorectal,breast and bladder cancers. There is also a high correlation betweenaurora-A and high histo-prognostic grade aneuploidy, making the kinase apotential prognostic vehicle. Inhibition of aurora kinase activity mayreduce cell proliferation, tumor growth and potentially tumorigenesis. Adetailed description of aurora kinase function is reviewed in Journal ofCell Science, 119, 3664-3675, 2006.

The Rho-associated coiled-coil-containing protein serine/threoninekinases ROCK-1 and ROCK-2 are thought to play a major role incytoskeletal dynamics by serving as downstream effectors of the Rho/Racfamily of cytokine- and growth factor-activated small GTPases. ROCKsphosphorylate various substrates, including, but not limited to, myosinlight chain phosphatase, myosin light chain, ezrin-radixin-moesinproteins and LIM (for Linl1, Isl1 and Mec3) kinases. ROCKs also mediatethe formation of actin stress fibers and focal adhesions in various celltypes. ROCKs have an important role in cell migration by enhancing cellcontractility and are required for tail retraction of monocytes andcancer cells. ROCK inhibitors have also been shown to reduce tumor-celldissemination in vivo. Recent experiments have defined new functions ofROCKs in cells, including centrosome positioning and cell-sizeregulation, which might contribute to various physiological andpathological states (Mueller et al, Nature Reviews Drug Discovery 4,387-398, 2005). The ROCK family members are attractive interventiontargets for a variety of pathologies including cancer and cardiovasculardisease. ROCK inhibitors can be useful therapeutic agents forhypertension, angina pectoris, and asthma. Furthermore, Rho is expectedto play a role in peripheral circulation disorders, arteriosclerosis,inflammation, and autoimmune disease and as such, is a useful target fortherapy (Shimokawa et al, Arteriosclerosis, Thrombosis, and VascularBiology, 25, 1767-1775, 2005).

The limited success of pharmacotherapeutic approaches in spinal-cordinjury is based to a large extent on the inability of injured nervefibers in the white matter of the human spinal cord to regrow andre-establish synaptic contacts with their disconnected partner neurons.A hostile micro-environment, characterized by the presence of a largevariety of molecular neurite-growth inhibitors at the lesion site, inthe scar tissue and on CNS myelin, accounts for this irreversible arrestof neurite-growth. In tissue culture, these inhibitors of neurite growthoften induce very dramatic responses, including the collapse of theformation and withdrawal of the neurite. Scar tissue in the human brainand spinal cord is a strong and persistent barrier for any regenerativeneurite growth and ROCK inhibitors might help injured fibers to grow orsprout beyond this regeneration-inhibiting tissue. A variety of evidenceindicates that injury to brain and spinal cord results in a stronglyactivated RhoA-ROCK pathway. Due to the persistent presence of theneurite growth inhibitors at or around the lesion site and in CNSmyelin, such activation could potentially persist for a long time,making ROCK inhibition an attractive goal not only for acute andsub-acute treatment, but also for chronic treatment of spinal-cordinjury. Inhibition of ROCK by two different small-molecule ROCKinhibitors (Y-27632 and fasudil) stimulated or accelerated functionalrecovery in different mouse and rat spinal-cord-injury models when givenlocally or systemically immediately after injury as a single dose orover several weeks (Dergham, P. et al. Rho signaling pathway targeted topromote spinal cord repair. J. Neurosci. 22, 6570-6577, 2002; Hara, M.et al. Protein kinase inhibition by fasudil hydrochloride promotesneurological recovery after spinal cord injury in rats. J. Neurosurg.Spine 93, 94-101, 2000. Fournier, A. E. et al. ROCK inhibition enhancesaxonal regeneration in the injured CNS. J. Neurosci. 23, 1416-1423,2003; Sung, J. K. et al. A possible role of RhoA/Rho-kinase inexperimental spinal cord injury in rat Brain Res. 959, 29-38, 2003;Tanaka, H. et al. Cytoplasmic p21(Cip1/WAF1) enhances axonalregeneration and functional recovery after spinal cord injury in rats.Neuroscience 127, 155-164, 2004). In these studies, ROCK inhibition notonly enhanced nerve-fiber growth beyond the lesion site, but was alsoneuroprotective and decreased tissue damage and cavity formation. On thebasis of these rodent studies, ROCK inhibitors, which possessneuroprotective and neuroregeneration-stimulating activities, couldoffer significant benefit for spinally injured patients. In addition,they could normalize spinal blood flow due to their vasodilatoryeffects, thereby further enhancing tissue preservation.

Pathologically, Alzheimer's disease is characterized at the microscopiclevel by intracellular neurofibrillary tangles and extracellular amyloidaggregates. Neurofibrillary tangles contain aberrantly phosphorylatedtau protein, a microtubule-associated protein and substrate for ROCK,whereas the amyloid aggregates are formed primarily by toxic42-amino-acid long amyloid-β(Aβ) peptides. It was recently shown (Zhou,Y. et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenicAβ42 by inhibiting Rho. Science 302, 1215-1217, 2003) that in cellssecreting Aβ42 and in transgenic PDAPP MICE producing large amounts ofAβ42, some NSAIDs lowered Aβ42 by inhibiting the RhoA-ROCK pathway. TheROCK inhibitor Y-27632 was effective in lowering Aβ42 levels both incell culture and in PDAPP transgenic mice after intra-cerebroventricularinjection. Activation of Rho by geranylgeranylpyrophosphate, a lipidrequired for the membrane attachment of Rho, increased Aβ42 levels; thisincrease was completely prevented by Y-27632. The ROCK inhibitor Y-27632used in animal Alzheimer's disease models was efficient in lowering theamount of the toxic Aβ42 levels, but had no effect on total Aβ levelsand this effect of Rho or ROCK inhibitors is at least one mechanism bywhich NSAIDs reduce Aβ42 levels. In addition to many other therapeuticinterventions, these inhibitors have the well-documented advantage ofstimulating regenerative growth of neuritis and it is therefore possiblethat the inhibition of this pathway could result in repair of theamyloid-damaged neural circuitry.

Most important in disease pathogenesis is the migration of leukocytesbeyond the brain endothelium into the CNS and the inflammatory cascadestimulated by these cells, which finally results in demyelination of CNSfiber tracts and in neurite damage and loss. Leukocytes require activeRhoA and ROCK for their journey beyond brain endothelium, because theirtrans-endothelial migration was prevented by the ROCK inhibitorY-2763294.

Neuroprotective activities of the ROCK inhibitors fasudil andhydroxy-fasudil are not restricted to spinal-cord injury models, buthave also been reported in cerebral multi-infarct models in gerbils andrats (Toshima Y, Satoh S, Ikegaki I, Asano T. A new model of cerebralmicrothrombosis in rats and the neuroprotective effect of a Rho-kinaseinhibitor. Stroke 31, 2245-2250, 2000; Satoh, S. et al. Pharmacologicalprofile of hydroxy fasudil as a selective ROCK inhibitor on ischemicbrain damage. Life Sci. 69, 1441-1453, 2001; Kitaoka, Y. et al.Involvement of RhoA and possible neuroprotective effect of fasudil, aROCK inhibitor, in NMDA-induced neurotoxicity in the rat retina. BrainRes. 1018, 111-118, 2004). In rodent stroke models, several regenerationinhibitors, such as the ROCK-activating NgR1 complex and one of itsligands, NOGO-A, have been neutralized 24 hours or even 1 week afterinduction of a cerebral stroke and improved functional recovery has beenobserved (Lee, J. K., Kim, J. E., Sivula, M. & Strittmatter, S. M. Nogoreceptor antagonism promotes stroke recovery by enhancing axonalplasticity. J. Neurosci. 24, 6209-6217, 2004; Wiessner, C. et al.Anti-Nogo-A antibody infusion 24 hours after experimental strokeimproved behavioral outcome and corticospinal plasticity in normotensiveand spontaneously hypertensive rats. J. Cereb. Blood FlowMetab. 23,154-165, 2003). Blocking ROCK is therefore a feasible neuroregenerativestrategy; furthermore, such a strategy has the advantage that thetherapeutic treatment window for the use of these inhibitors might belarger than for thrombolytic or neuroprotective stroke treatmentoptions.

Neuronal injuries in the peripheral nervous system or in the CNS ofhumans can lead to a chronic pain state known as neuropathic pain.Inflammatory mediators such as lysophosphatidic acid (LPA) which isproduced in response to injury has recently been shown to be involved ininitiation of neuropathic pain in a mouse model of peripheral nerveinjury (Inoue, M. et al. Initiation of neuropathic pain requireslysophosphatidic acid receptor signaling. Nature Med. 10, 712-718,2004). LPA is present at lesion sites in the PNS and CNS, and exerts itsfunction by binding to G-protein-coupled LPA receptors which results inactivation of the RhoA-ROCK pathway. The ROCK inhibitor Y-27632prevented the initiation of neuropathic pain after nerve injury or LPAinjection, whereas another ROCK inhibitor, H-1152, relieved neuropathicpain in an L5 spinal-nerve-transection model (Tatsumi, S. et al.Involvement of Rho-kinase in inflammatory and neuropathic pain throughphosphorylation of myristoylated alanine-rich C-kinase substrate(MARCKS). Neuroscience 131, 491-498, 2005). The results of these studiesindicate that ROCK is a potential drug target responsible for theinduction and also maintenance of persistent pain states.

Moreover, Schueller et al. (Abstract 1216, 8th World Congress onInflammation, Copenhagen, Denmark, Jun. 16-20, 2007) have demonstratedthat SLx-2119, an orally bioavailable, potent and highly selectiveinhibitor of ROCK 2 reduces atherogenesis in the presence ofdramatically elevated lipid levels in groups of 8 ApoE knockout mice,indicating that selective inhibition of ROCK 2 has the potential tolimit atherosclerosis.

The 70 kDa ribosomal S6 kinase (p70S6K) is activated by numerousmitogens, growth factors and hormones. Activation of p70S6K occursthrough phosphorylation at a number of sites and the primary target ofthe activated kinase is the 40S ribosomal protein S6, a major componentof the machinery involved in protein synthesis in mammalian cells. Inaddition, p70S6K activation has been implicated in cell cycle control,neuronal cell differentiation, regulation of cell motility and acellular response that is important in tumor metastases, immunity andtissue repair. Modulation of p70S6 kinase activity may also havetherapeutic implications in disorders such as cancer, inflammation, andvarious neuropathies. A detailed discussion of p70S6K kinases can befound in Prog. Cell Cycle Res., 1, 21-32, 1995, and Immunol Cell Biol.78, 447-51, 2000.

Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressedconstitutively active serine/threonine kinase that phosphorylatescellular substrates and thereby regulates a wide variety of cellularfunctions, including development, metabolism, gene transcription,protein translation, cytoskeletal organization, cell cycle regulation,and apoptosis. GSK-3 was initially described as a key enzyme involved inglycogen metabolism, but is now known to regulate a diverse array ofcell functions. Two forms of the enzyme, GSK-3+ƒ and GSK-3+ƒ, have beenpreviously identified. The activity of GSK-3+ƒ is negatively regulatedby protein kinase B/Akt and by the Wnt signaling pathway. Smallmolecules inhibitors of GSK-3 may, therefore, have several therapeuticuses, including the treatment and prevention of neurodegenerativediseases and stimulation of neurogeneration in various neurologicaldisorders (Gartner et al. J. Cell Science, 2006, 119, 3927-3934. Zhou etal. Neuron, 2004, 42, 897-912), type II diabetes, bipolar disorders,stroke, cancer, osteoarthritis, osteoporosis, rheumatoid arthritis(Cuzzocrea et al. Clinical Immunology, 2006, 120, 57-67) and chronicinflammatory disease. General review: Kockeritz et al., Current DrugTargets, 7, 1377-1388, 2006. Review of neurological applications:Current Drug Targets, 7(11), 1389-1397 and 1399-1409, 2006.

Protein kinases have become attractive targets for the treatment ofcancers (Fabbro et al., Pharmacology & Therapeutics 93:79-98, 2002). Ithas been proposed that the involvement of protein kinases in thedevelopment of human malignancies may occur by: (1) genomicrearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2)mutations leading to constitutively active kinase activity, such asacute myelogenous leukemia and gastrointestinal tumors, (3) deregulationof kinase activity by activation of oncogenes or loss of tumorsuppressor functions, such as in cancers with oncogenic RAS, (4)deregulation of kinase activity by over-expression, as in the case ofEGFR and (5) ectopic expression of growth factors that can contribute tothe development and maintenance of the neoplastic phenotype (Fabbro etal., Pharmacology & Therapeutics 93:79-98, 2002).

Cdc7 is a serine/threonine kinase that functions in the initiation ofDNA replication. Cdc7 is found in complexes with either Dbf4 or Drf1,regulatory subunits that are essential for activating the enzyme andtargeting it to substrates. Cdc7 phosphorylates multiple subunits of theminichromosome maintenance (MCM) DNA replicative helicase, therebyactivating it and triggering the unwinding of DNA double helixes atorigins of replication. This activity is essential to the properinitiation of DNA replication, the process by which a cell's DNA isduplicated prior to cell division. Inhibiting regulators of replicationinitiation, such as Cdc6, Cdc7/Dbf4 or Cdc7/Drf1, has lethalconsequences in cancerous cells, whereas normal cells are able to arrestand resume normal divisions once initiation activity is restored (Feng,D., et al. (2003). Inhibiting the expression of DNAreplication-initiation proteins induces apoptosis in human cancer cells.Cancer Res. 63, 7356-7364; Montagnoli, A., et al. (2004). Cdc7inhibition reveals a p53-dependent replication checkpoint that isdefective in cancer cells. Cancer Res 64, 7110-7116; see Lau, E., et al.(2006). Is there a pre-RC checkpoint that cancer cells lack? Cell Cycle5, 1602-1606, for review). Thus, small molecules that inhibit Cdc7 maybe useful therapeutic agents for the prevention and/or treatment ofcancer, inflammatory diseases, and other cell proliferative disorders.

Certain cancers are associated with angiogenesis. Angiogenesis is thegrowth of new capillary blood vessels from pre-existing vasculature(Risau, W., Nature 386:671-674, 1997). It has been shown that proteinkinases can contribute to the development and maintenance of theneoplastic phenotype (Fabbro et al., Pharmacology & Therapeutics93:79-98, 2002). For example, VEGF A-D and their four receptors havebeen implicated in phenotypes that involve neovascualrization andenhanced vascular permeability, such as tumor angiogenesis andlymphangiogenesis (Matter, A., Drug Discov. Today 6:1005-1023, 2001).

It has been recognized that a single agent approach that specificallytargets one kinase or one kinase pathway may be inadequate to treatdiseases and disorders, in particular cancer, for several reasons.Models have suggested that 5 to 7 mutations are necessary for theprogression of a normal cell to a malignant one. Furthermore, it iswidely recognized that cancer is the result of alterations in multiplepathways, in particular protein kinase pathways that are associated withprocesses such as cell growth, proliferation, apoptosis, motility, orinvasion. In a majority of cancers, a common feature is the simultaneousoverexpression and/or hyper-activation of a variety of protein kinases,such as receptor and non-receptor kinases, serine/threonine kinases, PI3kinases and cell cycle associated kinases. In fact, several of thesekinases, either alone or in conjunction with other kinases, have beenimplicated in a number of processes important for cell survival,proliferation, growth and malignant transformation, motility andinvasion leading to metastasis and angiogenesis or inflammation, anddiseases, disorders, and conditions associated therewith.

Accordingly, blocking one target kinase may not be clinically sufficientbecause there are multiple target kinases that affect the progression ofa condition, disease, or disorder. In addition, blocking one targetkinase may not be clinically sufficient because redundantkinase-mediated pathways and alternative oncogenic or inflammatorymechanisms may compensate for the blocked target kinase. Moreover, theuse of a single agent can also increase the chances that resistance tothat agent will develop.

Cardiovascular disease accounts for nearly one quarter of total annualdeaths worldwide. Vascular disorders such as atherosclerosis andrestenosis result from dysregulated growth of the vessel walls and therestriction of blood flow to vital organs. Various kinase pathways, e.g.JNK, are activated by atherogenic stimuli and regulated through localcytokine and growth factor production in vascular cells (Yang et al.,Immunity 9:575, 1998). Ischemia and ischemia coupled with reperfusion inthe heart, kidney or brain result in cell death and scar formation,which can ultimately lead to congestive heart failure, renal failure orcerebral dysfunction. In organ transplantation, reperfusion ofpreviously ischemic donor organs results in acute leukocyte-mediatedtissue injury and delay of graft function. Ischemia and reperfusionpathways are mediated by various kinases. For example, the JNK pathwayhas been linked to leukocyte-mediated tissue damage (Li et al., Mol.Cell. Biol. 16:5947-5954, 1996). Finally, enhanced apoptosis in cardiactissues has also been linked to kinase activity (Pombo et al., J. Biol.Chem. 269:26546-26551, 1994).

What is claimed is:
 1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein A is (ii)

R₁ is hydrogen or R_(a)R_(b)N; R₂ is hydrogen, heterocyclecarbonyl,alkylcarbonyl, arylcarbonyl, or R_(e)R_(f)N-alkyl-C(O)—; R₃ is alkyl,alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro,or R_(g)R_(h)N—; R_(a) and R_(b) are each hydrogen; R_(e) and R_(f) areeach independently hydrogen or alkyl; R_(g) and R_(h) are eachindependently hydrogen, alkyl, or alkylcarbonyl; R_(j) and R_(k) areeach independently hydrogen, alkyl, aryl, arylalkyl, or heteroaryl;R_(ii) is alkoxyalkyl, alkoxycarbonyl, aryl, arylalkyl,aryl(hydroxy)alkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy,cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl,heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,hydroxyalkyl, trialkylsilylalkyl, Z_(a)Z_(b)N—, Z_(a)Z_(b)Nalkyl- orZ_(c)Z_(d)NC(O)—; Z_(a) and Z_(b) are each independently hydrogen, alkylor H₂NalkylC(O)—; Z_(c) and Z_(d) are each independently hydrogen,alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroarylalkyl, heterocyclealkyl, hydroxyalkyl or dialkylN-alkyl-; m is0; and b is 1 or
 2. 2. The compound according to claim 1, wherein R₂ ishydrogen, or R_(e)R_(f)N-alkyl-C(O)—; R₄ is alkyl, alkoxyalkyl, aryl,cycloalkyl, R_(j)R_(k)N— or R_(j)R_(k)N-alkyl-; R₅ is alkyl, aryl orheteroaryl; R_(j) and R_(k) are each independently hydrogen, alkyl, oraryl; R_(ii) is alkoxyalkyl, aryl, arylalkyl, aryloxyalkyl,arylcarbonyl, arylthioalkyl, carboxy, cycloalkyl, cycloalkylalkyl,cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl,heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, Z_(a)Z_(b)Nalkyl-,or Z_(c)Z_(d)NC(O)—; Z_(a) and Z_(b) are each independently hydrogen oralkyl; Z_(c) and Z_(d) are each independently hydrogen, alkyl,alkoxyalkyl, aryl, arylalkyl, cycloalkylalkyl or heterocyclealkyl; m is0; and b is 1 or
 2. 3. The compound according to claim 1, wherein R₂ ishydrogen; R₄ is alkyl, alkoxyalkyl or aryl; R₅ is alkyl or aryl; R_(ii)is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl or halogen; b is 1 or 2;and m is
 0. 4. The compound according to claim 1, wherein R₄ isalkoxyalkyl, alkyl, aryl, or R_(j)R_(k)N—; R₅ is alkyl, aryl, orheteroaryl; R_(j) and R_(k) are alkyl; R_(ii) is alkoxyalkyl, aryl,arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl, arylcarbonyl,arylthioalkyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl,halogen, heteroaryl, heteroarylalkyl, heterocyclealkyl,heterocyclecarbonyl, hydroxyalkyl, Z_(a)Z_(b)Nalkyl or Z_(c)Z_(d)NC(O)—;Z_(a) and Z_(b) are each independently hydrogen or H₂Nalkyl-C(O)—; Z_(c)and Z_(d) are each independently hydrogen, alkoxyalkyl, alkyl,arylalkyl, cycloalkyl, cycloalkylalkyl, or heterocyclealkyl; b is 1; andm is
 0. 5. The compound according to claim 1, wherein R₂ is hydrogen,heterocyclecarbonyl, or arylcarbonyl; R₄ is alkyl, alkoxyalkyl, aryl,R_(j)R_(k)N— or R_(j)R_(k)N-alkyl-; R₅ is alkyl, or aryl; R_(j) andR_(k) are each independently hydrogen, alkyl, aryl, or arylalkyl; R_(ii)is aryl, arylalkyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl, halogen,heteroaryl, heterocyclealkyl, heterocyclecarbonyl, or Z_(c)Z_(d)NC(O)—;Z_(c) and Z_(d) are each independently hydrogen, alkyl, alkoxyalkyl,aryl; m is 0; and b is 1 or
 2. 6. The compound of claim 1, that isselected from the group consisting of:5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole;5-[1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;2-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile;3-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile;4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile;5-{1-[2-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;5-{1-[3-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;5-{1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;5-{1-[3-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;5-{1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;5-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; methyl3-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzoate; methyl4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzoate;5-[1-(2,4-dimethylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(3,5-dimethylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(2,3-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(2,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-(3,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-{1-[2,4-bis(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-4-yl)carbonyl]-1H-indazol-3-amine;5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazole;5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl)-1H-indazole;5-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazole;5-(4-benzyl-1H-1,2,3-triazol-1-yl)-1H-indazole;5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl)-1H-indazol-3-amine;5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-2-ol;5-[4-(methoxymethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]-1-phenylethanol;1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-2-ol;3-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-1-ol;1-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-1,2,3-benzotriazole;5-{4-[(phenylthio)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole;5-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1H-indazole;5-[4-(2-phenylethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;5-[4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;5-(4-cyclopentyl-1H-1,2,3-triazol-1-yl)-1H-indazole;1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]cyclohexanol;5-[4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole;5-[4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](phenyl)methanone;N,N-diethyl-N-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}amine;5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazole;5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine;N-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}-N′-(3-methylphenyl)urea;[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](3-chlorophenyl)methanone;[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](cyclopropyl)methanone;5-[5-cyclopropyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;N¹-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]methyl}glycinamide;(4-fluorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;(4-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;(3-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;(2-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;cyclopentyl[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone;1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid;5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl](tetrahydro-2H-pyran-4-yl)methanone;5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-{1-benzyl-5-[(4-methylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-ol;1-acetyl-5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;1-benzyl-4-(1H-indazol-5-yl)-N,N-dimethyl-1H-1,2,3-triazole-5-carboxamide;N,1-dibenzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;2-{2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]ethyl}-1H-isoindole-1,3(2H)-dione;5-{4-[(2,4-dichlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole;5-{4-[(2,6-dichlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole;5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;1-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indazole;5-[1-benzyl-5-(piperidin-1-ylcarbonyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;5-[1-benzyl-5-(morpholin-4-ylcarbonyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;5-[1-benzyl-5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;5-{1-benzyl-5-[3-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;5-{1-benzyl-5-[4-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;N-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}acetamide;N-{4-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}acetamide;5-{1-benzyl-5-[3-(1H-pyrazol-1-yl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;5-[1-benzyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]-N-phenylbenzamide;3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]-N-benzylbenzamide;5-[1-benzyl-5-(1-methyl-1H-indol-5-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;5-[1-benzyl-5-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;5-[1-benzyl-5-(3-morpholin-4-ylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine;1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-amine;3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenol;3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]benzamide;5-{1-benzyl-5-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine;1-benzyl-4-(1H-indazol-5-yl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-triazole-5-carboxamide;1-benzyl-4-(1H-indazol-5-yl)-N-(2-isopropoxyethyl)-1H-1,2,3-triazole-5-carboxamide;1-benzyl-4-(1H-indazol-5-yl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-triazole-5-carboxamide;1-benzyl-4-(1H-indazol-5-yl)-N-(tetrahydrofuran-3-ylmethyl)-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-cyclopentyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-(cyclopentylmethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-ethyl-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;1-benzyl-4-(1H-indazol-5-yl)-N-isopropyl-N-methyl-1H-1,2,3-triazole-5-carboxamide;1-benzyl-4-(1H-indazol-5-yl)-N-(2-methoxyethyl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;1-benzyl-4-(1H-indazol-5-yl)-N-phenyl-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-(4-chlorophenyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;1-benzyl-4-(1H-indazol-5-yl)-N-(2-morpholin-4-ylethyl)-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-[2-(dimethylamino)ethyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-(2-hydroxyethyl)-4-(1H-indazol-5-yl)-N-propyl-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-[3-(dimethylamino)propyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-[2-(diethylamino)ethyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide;N,1-dibenzyl-N-ethyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;N,1-dibenzyl-N-(2-hydroxyethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;(3R)-1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-3-ol;1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidine-4-carboxamide;5-{1-benzyl-5-[(2,6-dimethylmorpholin-4-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;5-{5-[(4-acetylpiperazin-1-yl)carbonyl]-1-benzyl-1H-1,2,3-triazol-4-yl}-1H-indazole;5-{1-benzyl-5-[(4-phenylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;1-benzyl-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;1-benzyl-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide;and1-benzyl-N-[3-(1H-imidazol-1-yl)propyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide.7. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) according to claim 1, in combinationwith a pharmaceutically suitable carrier.